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WO2006068617A1 - A new manufacturing process for the preparation of halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione - Google Patents

A new manufacturing process for the preparation of halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione Download PDF

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WO2006068617A1
WO2006068617A1 PCT/SE2005/002019 SE2005002019W WO2006068617A1 WO 2006068617 A1 WO2006068617 A1 WO 2006068617A1 SE 2005002019 W SE2005002019 W SE 2005002019W WO 2006068617 A1 WO2006068617 A1 WO 2006068617A1
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process according
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acid
manufacturing
chloro
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French (fr)
Inventor
Sahar Abbas
Stuart Norman Lile Bennett
Simon Nicholas Black
Catherine J. Brear
Louis Diorazio
Michael D. Golden
Ruth Kr Moyes
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new process for the preparation of halogen substituted A- hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5 , 10-tetrahydropyridaz ⁇ io[4,5-b] quinoline- 1,10- dione using a diacid intermediate.
  • the invention relates to new intermediates prepared therein suitable for manufacturing of halogen substituted 4-hydroxy-2-(2-chloro-4- methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10-dione and to the use of the intermediates for the manufacturing of a pharmaceutically active compound.
  • Halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)- 1,2,5,10- tetrahydropyridazino[4,5-b]quinoline-l,10-diones exhibit the property of binding to the NMDA receptor glycine site has a utility for the amelioration of pain and particularly for the amelioration of neuropathic pain. This is especially true for compound 7-chloro-4- hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5, 10-tetrahydropyridazino[4,5- ⁇ ]quinoline- 1,10- dione.
  • halo is chloro, fluoro or bromo.
  • WO 95/11244 describes the synthesis of pyridazino quinoline compounds.
  • WO 01/47927 describes a method of preparation for compound 7-chloro-4-hydroxy-2-(2- chloro-4-methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5- ⁇ ]quinoline-l,10-dione.
  • This method employs an inefficient four stage synthesis from methyl-2-amino-4- chlorobenzoate to reach the key intermediate Acid Amide with an overall yield to this intermediate of only 17%.
  • WO 01/47927 also describes the conversion of the Acid Amide to the compound of 5 formula A in an inefficient two step process (via the isolated intermediate Acyl Hydrazide), and uses an expensive coupling reagent, CMC and an environmentally undesirable solvent DCM. Further the relative volumes used are large, yields are low (54% across the two stages) and the reaction time for the coupling in this prior art process are over 20 hours.
  • the present invention provides for a new process to 7-chloro-4-hydiOxy-2-(2-chloro-4- methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5- ⁇ ]quinoline-l,10-dione . Further, it provides for new intermediates and a process to prepare-said intermediates, especially with regard to large-scale manufacturing.
  • Step 1 One embodiment of the invention relates to a process for the manufacturing of Diacid comprising steps Ia, Ib and Ic as described below;
  • DMAD Dimethyl acetylenedicarboxylate
  • MACB 2-amino-4- chlorobenzoate
  • DMAD is slowly added to an agitated solution of MACB in methanol.
  • the mixture is stirred to generate the intermediate Michael Adduct (1C).
  • the reaction mixture is cooled and aqueous KOH is cautiously added. After a solvent swap into water, the di-potassium salt of the Diacid is generated.
  • the batch is cooled and the reaction mixture is slowly added to an aqueous hydrochloric acid to liberate the Diacid as a solid.
  • the product is isolated by filtration, washed with water and dried under vacuum.
  • step Ib is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium t-butoxide and sodium methoxide.
  • step Ia is selected from the group consisting of methanol, ethanol, propanol, butanol, THF or acetonitrile.
  • step Ic is selected from the group consisting of hydrochloric acid, sulphuric acid or its salts, methanesulphonic acid, acetic acid, phosphoric acid or other suitable acids.
  • the reaction time on laboratory scale is approximately 10 hours (disregarding drying time of the solid product).
  • the yield of the Diacid process may be between 85 and 95 %.
  • One embodiment of the invention relates to a process for the manufacturing of Acid Amide (2C) comprising steps 2a and 2b as described below;
  • the Diacid is slurried with triethylamine in NMP. Acetic anhydride is added, followed by pyrrolidine. Water and aqueous hydrochloric acid are then added to precipitate the product, which is filtered and washed with aqueous NMP and then acetonitrile.
  • the base in step 2a is selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tributylamine and N-methyl-piperidine.
  • the solvent is selected from the group comprising acetonitrile, N-methyl-2-pyrrolidinone (NMP) or toluene, DMF, sulpholane or DMSO.
  • the mixture is heated to a temperature up to about 80 0 C, preferably around 5O 0 C during the cyclisation and amide formation. In one embodiment the temperature is between 4O 0 C and 6O 0 C.
  • the reaction time on laboratory scale is approximately 6 hours (disregarding drying time of the solid product).
  • the yield of the Acid Amide process may be between 85 and 95 %.
  • step 2 is among others that in combination with step 1, that this provides a much more efficient processing route to the intermediate Acid Amide. Only two steps are required, the overall yield for the two steps is higher (>80%), processing times are much shorter and the two processes are more concenirated (allowing for greater batch sizes and less solvent waste).
  • One embodiment of the invention relates to a process for the manufacturing of compounds of formula A comprising steps 3 a and 3b as described below;
  • a mixture of Acid Amide (3A) and Boc Hydrazine (3B), toluene and N 1 N- diisopropylethylamine is concentrated to remove water.
  • Pivaloyl chloride is added, followed by acetonitrile and water.
  • the mixture is separated, and the organic phase is added to a solution of methanesulphonic acid in acetonitrile before solvent swapping into acetonitrile.
  • Water is added to crystallize the compound of formula A, which is washed with aqueous acetonitrile then IMS and dried under vacuum.
  • the organic solvent in step 3 a is selected from the group consisting of N-methylpyrrolidinone, heptane, cyclohexane, sulpholane, methyl isobutylketone, ethyl acetate, butyl acetate and isopropyl acetate, THF or mixtures thereof.
  • the base used in step 3 a is selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tributylamine and N-methyl-piperidine
  • the temperature of the solution during the pivaloyl chloride addition in step 3a is approximately 70 0 C.
  • the coupling product mixture is added to a solution of acid (instead of the other way round), which provides for a cleaner reaction profile (step 3b).
  • the precipitation of the product in step 3b is from aqueous acetonitrile at 5O 0 C.
  • the cyclisation solvent is selected from a group comprising of acetonitrile, toluene, THF, heptane, and cyclohexane.
  • Advantages of step 3 is the use of a much cheaper coupling agent (pivaloyl chloride), non- isolation of the Acyl Hydrazide intermediate and an improvement in yield (to >65% in a single step). Processing time (from Acid Amide to compound of formula A) is reduced and the process is more concentrated. The need for an environmentally undesirable solvent (DCM) is eliminated and less solvent waste is generated overall.
  • DCM environmentally undesirable solvent
  • halo is fluoro, chloro or bromo.
  • Another embodiment of the invention related to diacid wherein halo is chloride.
  • a further embodiment of the invention relates to intermediate 3Db
  • One embodiment of the invention relates to the use of the compounds IA to ID, Diacid, 2B to 2C and 3A to 3D as defined above, as intermediates for the manufacturing of compounds of formula A, especially for the manufacturing of 7-chloro-4-hydroxy-2-(2- chloro-4-methylphenyl)- 1 ,2,5, 10-tetrahydropyridazino[4,5-b]quinoline-l , 10-dione.
  • Another embodiment of the invention related to the use of the process as defined above for the large scale manufacturing of compounds of formula A.
  • One embodiment of the invention relates to the use of the compounds IA to ID, 2A to 2C and 3 A to 3Db as defined above, as intermediates for the manufacturing of a pharmaceutically active compound.
  • Another embodiment of the invention relates to the use of the intermediate compounds IA to ID, 2A to 2C and 3 A to 3Db as defined above, prepared according to the process described above under step 1, 2 and 3, for the manufacturing of a medicament for the treatment of pain.
  • Acid Amide (50.0Og 5 0.1559 mol), BOC Hydrazine (4Og, 0.1559 mol), N, N- diisopropylethylamine (81.5 ml, 0.4677 mol) and toluene (500ml) were mixed together and distilled at 250mbar to remove 100ml of solvent. The temperature of the dry solution was then adjusted to 70 0 C and pivaloyl chloride (43.2ml, 0.3508 mol) was slowly added under nitrogen. The reaction mixture was held at 70 0 C for two hours before adding acetonitrile (150ml) and water (250ml).
  • the resulting two-phase mixture was separated at 5O 0 C and the upper organic layer then added slowly to a solution of methanesulphonic acid (50.6ml, 0.7795mols) in acetonitrile (250ml) maintaining 40 0 C.
  • the reaction mixture was then distilled at 250mbar to remove 550ml of solvent before adding acetonitrile (550ml).
  • the reaction mixture was again distilled at 250mbar to remove 550ml of solvent before adding acetonitrile (350ml).
  • the temperature of the reaction mixture was adjusted to 50 0 C the,n water (200ml) was slowly added to precipitate the product.
  • the product slurry was filtered at 50 0 C, washed with aqueous acetonitrile (1:1, 2 x 100ml), then IMS (2 x 100ml) and dried at 50 0 C ( ⁇ 250mbar) to afford the product as a solid (44.5g, 93.4%w/w, 0.1071 mol, 68.6%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The present invention relates to a new process for the preparation of halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione using a diacid intermediate. The invention relates to new intermediates prepared therein suitable for manufacturing of halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione and to the use of the intermediates for the manufacturing of a pharmaceutically active compound.

Description

A new manufacturing process for the preparation of halogen substituted 4-hydroxy-2- (2-chloro-4-methylphenyl) -I12 , 5 , 10- tetrahydropyridazino [4 , 5 -b] quinoline- 1 , 10 -d'ione .
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of halogen substituted A- hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5 , 10-tetrahydropyridazήio[4,5-b] quinoline- 1,10- dione using a diacid intermediate. The invention relates to new intermediates prepared therein suitable for manufacturing of halogen substituted 4-hydroxy-2-(2-chloro-4- methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10-dione and to the use of the intermediates for the manufacturing of a pharmaceutically active compound.
BACKGROUND TO THE INVENTION
Halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)- 1,2,5,10- tetrahydropyridazino[4,5-b]quinoline-l,10-diones exhibit the property of binding to the NMDA receptor glycine site has a utility for the amelioration of pain and particularly for the amelioration of neuropathic pain. This is especially true for compound 7-chloro-4- hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5, 10-tetrahydropyridazino[4,5-ό]quinoline- 1,10- dione.
The structural formula of halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5,10-tetrahydropyridazino[4,5-έ]quinoline- 1 , 10-dione is;
Figure imgf000002_0001
wherein: halo is chloro, fluoro or bromo.
WO 95/11244 describes the synthesis of pyridazino quinoline compounds.
WO 01/47927 describes a method of preparation for compound 7-chloro-4-hydroxy-2-(2- chloro-4-methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5-δ]quinoline-l,10-dione. This method employs an inefficient four stage synthesis from methyl-2-amino-4- chlorobenzoate to reach the key intermediate Acid Amide with an overall yield to this intermediate of only 17%.
WO 01/47927 also describes the conversion of the Acid Amide to the compound of 5 formula A in an inefficient two step process (via the isolated intermediate Acyl Hydrazide), and uses an expensive coupling reagent, CMC and an environmentally undesirable solvent DCM. Further the relative volumes used are large, yields are low (54% across the two stages) and the reaction time for the coupling in this prior art process are over 20 hours.
10
Thus, there is a need for a more convenient and more economically efficient process for the manufacturing of large scale quantities of pharmaceutical quality of halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5, 10-tetrahydropyridazino[4,5-b]quinoline- 1,10-dion, where factors like costs, yields, manufacturing time, use of more is environmentally friendly solvents, etcetera are vital for commercial application. The present invention provides for such a process.
DETAILED DESCRIPTION OF THE INVENTION
2.0
The present invention provides for a new process to 7-chloro-4-hydiOxy-2-(2-chloro-4- methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5-έ]quinoline-l,10-dione . Further, it provides for new intermediates and a process to prepare-said intermediates, especially with regard to large-scale manufacturing.
25
The new manufacture process of halogen substituted 4-hydroxy-2-(2-chloro-4- methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10-dione (compound A) is described below.
3o Step 1 One embodiment of the invention relates to a process for the manufacturing of Diacid comprising steps Ia, Ib and Ic as described below;
Figure imgf000004_0001
halo = F, Cl or Br Michael Adduct , 1 C
Figure imgf000004_0002
1D
The starting materials Dimethyl acetylenedicarboxylate (DMAD) and methyl 2-amino-4- chlorobenzoate (MACB) are commercially available from Aldrich and Lancaster respectively.
DMAD is slowly added to an agitated solution of MACB in methanol. The mixture is stirred to generate the intermediate Michael Adduct (1C). The reaction mixture is cooled and aqueous KOH is cautiously added. After a solvent swap into water, the di-potassium salt of the Diacid is generated. The batch is cooled and the reaction mixture is slowly added to an aqueous hydrochloric acid to liberate the Diacid as a solid. The product is isolated by filtration, washed with water and dried under vacuum.
One embodiment relates to the process of the invention whereby the base in step Ib is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium t-butoxide and sodium methoxide.
Another embodiment relates to the process of the invention whereby the solvent in step Ia is selected from the group consisting of methanol, ethanol, propanol, butanol, THF or acetonitrile. Another embodiment relates to the process of the invention whereby the acid in step Ic is selected from the group consisting of hydrochloric acid, sulphuric acid or its salts, methanesulphonic acid, acetic acid, phosphoric acid or other suitable acids.
Another embodiment relates to the process of the invention whereby the di-potassium salt is added to the acid solution and the temperature of the acid solution is approximately
50°C.
The reaction time on laboratory scale is approximately 10 hours (disregarding drying time of the solid product).
The yield of the Diacid process may be between 85 and 95 %.
Step 2
One embodiment of the invention relates to a process for the manufacturing of Acid Amide (2C) comprising steps 2a and 2b as described below;
Figure imgf000005_0001
2C (=3A)
The Diacid is slurried with triethylamine in NMP. Acetic anhydride is added, followed by pyrrolidine. Water and aqueous hydrochloric acid are then added to precipitate the product, which is filtered and washed with aqueous NMP and then acetonitrile. In one embodiment of the invention is the base in step 2a is selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tributylamine and N-methyl-piperidine. In another embodiment of the invention the solvent is selected from the group comprising acetonitrile, N-methyl-2-pyrrolidinone (NMP) or toluene, DMF, sulpholane or DMSO.
In yet another embodiment of the process of the invention the mixture is heated to a temperature up to about 800C, preferably around 5O0C during the cyclisation and amide formation. In one embodiment the temperature is between 4O0C and 6O0C.
The reaction time on laboratory scale is approximately 6 hours (disregarding drying time of the solid product).
The yield of the Acid Amide process may be between 85 and 95 %.
Advantages of step 2 are among others that in combination with step 1, that this provides a much more efficient processing route to the intermediate Acid Amide. Only two steps are required, the overall yield for the two steps is higher (>80%), processing times are much shorter and the two processes are more concenirated (allowing for greater batch sizes and less solvent waste).
Step 3
One embodiment of the invention relates to a process for the manufacturing of compounds of formula A comprising steps 3 a and 3b as described below;
Figure imgf000006_0001
A mixture of Acid Amide (3A) and Boc Hydrazine (3B), toluene and N1N- diisopropylethylamine is concentrated to remove water. Pivaloyl chloride is added, followed by acetonitrile and water. The mixture is separated, and the organic phase is added to a solution of methanesulphonic acid in acetonitrile before solvent swapping into acetonitrile. Water is added to crystallize the compound of formula A, which is washed with aqueous acetonitrile then IMS and dried under vacuum.
In one embodiment of the process of the invention the organic solvent in step 3 a is selected from the group consisting of N-methylpyrrolidinone, heptane, cyclohexane, sulpholane, methyl isobutylketone, ethyl acetate, butyl acetate and isopropyl acetate, THF or mixtures thereof.
In another embodiment of the process of the invention the base used in step 3 a is selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tributylamine and N-methyl-piperidine In yet another embodiment of the process of the invention the temperature of the solution during the pivaloyl chloride addition in step 3a is approximately 700C.
In yet a further embodiment of the process of the invention the coupling product mixture is added to a solution of acid (instead of the other way round), which provides for a cleaner reaction profile (step 3b). In one embodiment of the process of the invention the precipitation of the product in step 3b is from aqueous acetonitrile at 5O0C.
In another embodiment of the process the cyclisation solvent is selected from a group comprising of acetonitrile, toluene, THF, heptane, and cyclohexane. Advantages of step 3 is the use of a much cheaper coupling agent (pivaloyl chloride), non- isolation of the Acyl Hydrazide intermediate and an improvement in yield (to >65% in a single step). Processing time (from Acid Amide to compound of formula A) is reduced and the process is more concentrated. The need for an environmentally undesirable solvent (DCM) is eliminated and less solvent waste is generated overall.
Intermediates
One embodiment of the invention relates to intermediate Diacid
Figure imgf000008_0001
wherein halo is fluoro, chloro or bromo.
Another embodiment of the invention related to diacid wherein halo is chloride.
A further embodiment of the invention relates to intermediate 3Db
Figure imgf000008_0002
3Db wherein halo is fluoro, chloro or bromo and P is
Figure imgf000008_0003
Yet another embodiment of the invention related to intermediate 3Db wherein halo is chloride.
Use
One embodiment of the invention relates to the use of the compounds IA to ID, Diacid, 2B to 2C and 3A to 3D as defined above, as intermediates for the manufacturing of compounds of formula A, especially for the manufacturing of 7-chloro-4-hydroxy-2-(2- chloro-4-methylphenyl)- 1 ,2,5, 10-tetrahydropyridazino[4,5-b]quinoline-l , 10-dione. Another embodiment of the invention related to the use of the process as defined above for the large scale manufacturing of compounds of formula A.
Medical Use
One embodiment of the invention relates to the use of the compounds IA to ID, 2A to 2C and 3 A to 3Db as defined above, as intermediates for the manufacturing of a pharmaceutically active compound.
Another embodiment of the invention relates to the use of the intermediate compounds IA to ID, 2A to 2C and 3 A to 3Db as defined above, prepared according to the process described above under step 1, 2 and 3, for the manufacturing of a medicament for the treatment of pain.
Examples
The invention will now be illustrated by the following Examples in which, generally : (i) operations were carried out at ambient temperature, i.e. in the range 17 to 250C and under an atmosphere of an inert gas such as argon unless otherwise stated;
(ii)evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (iii) yields, where present, are not necessarily the maximum attainable; (iv) in general, the structures of the end-products of the Formula A were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral (MS) techniques; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Bruker spectrometer operating at a field strength of 400MHz; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; (vi) intermediates were not necessarily fully purified but their structures and purity were assessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis; (vii)the following abbreviations have been used:- NMP N-methylpyrrolidinone
5
Step 1 -Diacid
To a stirred solution of methyl 2-amino-4-chlorobenzoate (50.00 g, 0.2681 mol) in methanol (400 ml) under nitrogen held at 60°C, was slowly added dimethyl acetylenedicarboxylate (40.4 ml, 0.3217 mol). The reaction mixture was heated to reflux o and held for at least 6 hours. Aqueous potassium hydroxide (122.8 g, 1.0724 mol) was slowly added then water (50ml) and the reaction mixture distilled under atmospheric pressure to remove 250ml of distillates. Water (250ml) was added and the distillation was repeated to remove a further 250ml of distillates. Water (50ml) was added and the reaction solution was then transferred into a solution of aqueous hydrochloric acid (90ml, 1.0724 s mol) in water (100ml) held at 50°C to precipitate the product. The product slurry was filtered at 50°C and washed with water (2 x 100ml) and acetonitrile (2 x 100ml), then dried at 50°C (<250mbar) to afford the product as a solid (76.95g, 91.7%w/w, 0.247 lmol, 88%). 1H NMR (400MHz, DMSO + TFA) δ 8.26 (d, J = 8.8 Hz, IH), 7.83 (s, IH), 7.60 (d, J = 8.7 Hz, IH); MS (CI) : 268 (M+H). o
Step 2 -Acid Amide
To a stirred solution of Diacid (69.82 g @ 93.1%w/w, 0.2277 mol) and triethylamine (95 ml) in NMP (325ml) held at 5O0C, was slowly added acetic anhydride (64 ml, 0.6831 mol). The reaction mixture was held at 500C for 2 hours before slowly adding pyrrolidine (48 ml, 5 05693 mol). The reaction solution was held for 30 minutes at 500C before cooling to
200C. Water (325 ml) was added maintaining 200C, then hydrochloric acid (86 ml, 1.0247 mol), again at 500C. The resulting product slurry was cooled to 5°C and collected by filtration before being washed by aqueous NMP (1:1, 130ml) then acetonitrile (3 x 130ml). The product was dried at 600C (<250mbar) to afford the product as a solid (72.99g, 0 98.6%w/w, 0.2244mol, 93.6%). 1H NMR (400MHz, DMSO + TFA) δ 8.30 (d, J = 8.8 Hz, IH), 7.80 (s, IH), 7.63 (d, J = 8.7 Hz, IH), 3.54-3.58 (m, 2H), 3.20-3.23 (m, 2H), 1.83-1.97 (m, 4H); MS (CI) : 321 (M+H).
Step 3 - Compound A
Acid Amide (50.0Og5 0.1559 mol), BOC Hydrazine (4Og, 0.1559 mol), N, N- diisopropylethylamine (81.5 ml, 0.4677 mol) and toluene (500ml) were mixed together and distilled at 250mbar to remove 100ml of solvent. The temperature of the dry solution was then adjusted to 700C and pivaloyl chloride (43.2ml, 0.3508 mol) was slowly added under nitrogen. The reaction mixture was held at 700C for two hours before adding acetonitrile (150ml) and water (250ml). The resulting two-phase mixture was separated at 5O0C and the upper organic layer then added slowly to a solution of methanesulphonic acid (50.6ml, 0.7795mols) in acetonitrile (250ml) maintaining 400C. The reaction mixture was then distilled at 250mbar to remove 550ml of solvent before adding acetonitrile (550ml). The reaction mixture was again distilled at 250mbar to remove 550ml of solvent before adding acetonitrile (350ml). The temperature of the reaction mixture was adjusted to 500C the,n water (200ml) was slowly added to precipitate the product. The product slurry was filtered at 500C, washed with aqueous acetonitrile (1:1, 2 x 100ml), then IMS (2 x 100ml) and dried at 500C (<250mbar) to afford the product as a solid (44.5g, 93.4%w/w, 0.1071 mol, 68.6%).
1H ΝMR (400MHz, DMSO + TFA) δ 8.15 (d, J = 8.7 Hz, IH)5 8.07 (s, IH)5 7.40-7.45 (m, 3H), 7.26 (d, J = 8.4 Hz5 IH)5 2.37 (s, 3H); MS (CI) : 388 (M+H).

Claims

1. A process for the manufacturing of Diacid comprising steps Ia, Ib and Ic
Figure imgf000012_0001
halo = F, Cl or Br Michael Adduct , 1C
Figure imgf000012_0002
1D
2. A process for the manufacturing of Acid Amide comprising steps 2a and 2b
Figure imgf000012_0003
wherein P is
Figure imgf000012_0004
Figure imgf000012_0005
2C (=3A) wherein halo is F, Cl αr Br.
3. A process for the manufacturing of compounds of formula A comprising steps 3 a and 3b
Figure imgf000013_0001
4. The process according to any one of claims 1 to 3 wherein halogen is chloro.
5
5. The process according to any one of claims 1 or 4 whereby the base in step Ib is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium t-butoxide and sodium methoxide.
o 6. The process according to any one of claims 1 or 4 whereby the solvent in step Ia is selected from the group consisting of methanol, ethanol, propanol, butanol, THF or acetonitrile.
7. The process according to any one of claims 1 or 4 whereby the acid in step Ic is selected s from the group consisting of hydrochloric acid, sulphuric acid or its salts, methanesulphonic acid, acetic acid, phosphoric acid or other suitable acids.
8. The process according to any one of claims 1 or 4 whereby the di-potassium salt is added to the acid solution and the temperature of the acid solution is approximately 500C. o
9. The process according to any one of claims 2 or 4 whereby the base in step 2a may be selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tributylamine and N-methyl-piperidine.
10. The process according to any one of claims 2 or 4 whereby the solvent is selected from the group comprising acetonitrile, N-methyl-2-pyrrolidinone (NMP) or toluene, DMF, sulpholane or DMSO.
11. The process according to any one of claims 2 or 4 whereby the mixture is heated to a temperature between 400C and 60°C.
12. The process according to any one of claims 3 or 4 whereby the organic solvent in step 3 a is selected from the group consisting of N-methylpyrrolidinone, heptane, cyclohexane, sulpholane, methyl isobutylketone, ethyl acetate, butyl acetate and isopropyl acetate, THF or mixtures thereof.
13. The process according to any one of claims 3 or 4 whereby the base used in step 3a is. selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tribulyiamine and N-methyl-piperidine ,\
14. The process according to any one of claims 3 or 4 whereby the temperature of the solution during the pivaloyl chloride addition in step 3a is approximately 700C.
15. The process according to any one of claims 3 or 4 whereby the precipitation of the product in step 3b is from aqueous acetonitrile at 500C.
16. The process according to any one of claims 3 or 4 whereby the cyclisation solvent is selected from a group comprising of acetonitrile, toluene, THF, heptane, and cyclohexane.
17. Use of the process according to any one of claims 1 to 16 for the large scale manufacturing of the compounds of formula A.
18. Use of the compounds IA to ID, 2A to 2C and 3A to 3Db,as defined in any one of claims 1 to 4, as an intermediate for the manufacturing of a pharmaceutically active compound.
19. Use of intermediate compounds IA to ID, 2 A to 2C and 3 A to 3Db as defined in claim any one of claims 1 to 4, prepared according to the process described under steps 1, 2 and 3, for the manufacturing of a medicament for the treatment of pain.
20. The compound
Figure imgf000015_0001
Diacid
wherein halo is fluoro, chloro or bromo.
21. The compound
Figure imgf000015_0002
3Db wherein halo is fluoro, chloro or bromo and P is
Figure imgf000015_0003
PCT/SE2005/002019 2004-12-23 2005-12-22 A new manufacturing process for the preparation of halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione Ceased WO2006068617A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047926A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Compounds and methods for the treatment of pain
WO2001047924A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Methods and compositions for the treatment of pain
WO2001047524A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Method and composition for the treatment of pain
WO2001047923A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Compounds and methods for the treatment of pain
WO2001047523A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Method and composition for the treatment of pain
WO2001047927A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Compound and method for the treatment of pain

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047926A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Compounds and methods for the treatment of pain
WO2001047924A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Methods and compositions for the treatment of pain
WO2001047524A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Method and composition for the treatment of pain
WO2001047923A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Compounds and methods for the treatment of pain
WO2001047523A1 (en) * 1999-12-23 2001-07-05 Astrazeneca Ab Method and composition for the treatment of pain
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