WO2008107064A1 - New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6h)-one - Google Patents
New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6h)-one Download PDFInfo
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- WO2008107064A1 WO2008107064A1 PCT/EP2008/001080 EP2008001080W WO2008107064A1 WO 2008107064 A1 WO2008107064 A1 WO 2008107064A1 EP 2008001080 W EP2008001080 W EP 2008001080W WO 2008107064 A1 WO2008107064 A1 WO 2008107064A1
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- Prior art keywords
- methyl
- ethyl
- phenylbutane
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- chloro
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- YUQZAUWIHXYWKC-UHFFFAOYSA-N 3-methyl-4-phenyl-6h-[1,2]oxazolo[3,4-d]pyridazin-7-one Chemical compound CC=1ON=C(C(NN=2)=O)C=1C=2C1=CC=CC=C1 YUQZAUWIHXYWKC-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 22
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- CVBUKMMMRLOKQR-UHFFFAOYSA-N 1-phenylbutane-1,3-dione Chemical compound CC(=O)CC(=O)C1=CC=CC=C1 CVBUKMMMRLOKQR-UHFFFAOYSA-N 0.000 abstract description 9
- UXOLDCOJRAMLTQ-ZZXKWVIFSA-N ethyl (2e)-2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(\Cl)=N/O UXOLDCOJRAMLTQ-ZZXKWVIFSA-N 0.000 abstract description 3
- MIRRVOUGVODFOY-UHFFFAOYSA-N ethyl 4-benzoyl-5-methyl-1,2-oxazole-3-carboxylate Chemical compound CCOC(=O)C1=NOC(C)=C1C(=O)C1=CC=CC=C1 MIRRVOUGVODFOY-UHFFFAOYSA-N 0.000 abstract description 2
- 239000011541 reaction mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ADLLKZKXRJJBPP-UHFFFAOYSA-N 6h-[1,2]oxazolo[3,4-d]pyridazin-7-one Chemical class O=C1NN=CC2=CON=C12 ADLLKZKXRJJBPP-UHFFFAOYSA-N 0.000 description 1
- 241000208199 Buxus sempervirens Species 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
Definitions
- the present invention relates to a new process for preparing 3-methyl-4- phenylisoxazolo[3,4-d]pyridazin-7(6H)-one having the structure of formula (I):
- the compound of formula (I) is a useful intermediate in the preparation of some pyridazin- 3(2H)-one derivatives which are selective inhibitors of phosphodiesterase 4 (PDE4) which have been described, for example, in the international patent applications numbers WO 03/097613 A1 , WO 2004/058729 A1 and WO 2005/049581.
- PDE4 phosphodiesterase 4
- the second article reports a yield of 40%.
- step (I) subsequently reacting the product from step (a) with hydrazine or an hydrate thereof to yield 3-methyl-4-phenyl ⁇ soxazolo[3,4-d]pyridaz ⁇ n-7(6H)-one (I)
- step (b) is carried out on the mixture resulting from step (a) without isolating ethyl 4-benzoyl-5-methyl ⁇ soxazole-3-carboxylate (Via) there from.
- the process of the invention proceeds by directly treating with hydrazine (or its hydrate) the reaction mixture obtained in step (a) without isolating the reaction product there from
- the reactions are carried out using a C1-C3 alkanol, preferably methanol as a solvent.
- step a) is carried by addition of alkali alcoholate, preferably sodium methoxide followed by ethyl 2-chloro-2- (hydroxy ⁇ mino)acetate.
- alkali alcoholate preferably sodium methoxide followed by ethyl 2-chloro-2- (hydroxy ⁇ mino)acetate.
- the molar ratio of ethyl 2-chloro-2- (hydroxyimino)acetate to 1 -phenylbutane-1 ,3-dione is comprised between 1 ,05 and 1 ,15
- the molar ratio of hydrazine hydrate to 1-phenylbutane-1 ,3-dione is comprised between 1 ,15 and 1 ,25.
- the reactants 1 -phenylbutane-1 ,3-dione (Ha), ethyl 2-chloro-2-(hydroxyimino)acetate (Ilia) and hydrazine hydrate used in the present invention are commercially available, for ex- ample from ABCR GmbH & CO. KG (P.O. Box 21 01 35, 76151 Düsseldorf, GERMANY), Aldrich Chemical Company, lnc (1001 West Saint Paul Avenue, Milwaukee, Wl 53233, USA) or Fluka Chemie GmbH (Industriestrasse 25, P O. Box 260, CH-9471 Buchs, SWITZERLAND).
- step (a) The preferred conditions for the process of step (a) are the following:
- 1- phenylbutane-1 ,3-dione is suspended in 300-350 ml of a C1 -C3 alkanol, preferably methanol, and the suspension is cooled to 10-15 0 C.
- a C1 -C3 alkanol preferably methanol
- 190-200 g of MeONa 30% (methanolic solution) per mol of 1-phenylbutane-1 ,3-dione are added dropwise over 20-40 min at 10-15 0 C and the addition funnel is washed with 10-20 ml. of methanol.
- the reaction mixture is stirred at 10-15°C for about 20-40 min and then cooled to 0-5 0 C.
- step (b) A solution of 166,7 g (1, 1 mol) ethyl 2-chloro-2-(hydroxyim ⁇ no)acetate in 300-350 mL of methanol are added dropwise over 50-70 min to the reaction mixture at 0-5 0 C and the addition funnel is washed with 10-20 mL of methanol.
- the preferred conditions for the process of step (b) are the following:
- reaction mixture from step a) is warmed to 20-25 0 C and stirred for 100-150 min. Then 1 ,2 mol of NH 2 NH 2 H 2 O are added dropwise over 10-20 min at 35-45°C, the addition funnel is washed with 10-20 ml_ MeOH and the reaction mixture is stirred at 35-45 0 C for
- HPLC HPLC
- DAD diode array detector
- ZMD ZQ mass detector
- HPLC method used a Symmetry C18 column (3.5 ⁇ m, 21x100 mm) and mobile phase was composed by two phases: Phase A: Buffered (Formic acid/ammonia) aqueous solution at pH: 3. Phase B: 50.50 mixture acetonitrile/metha ⁇ ol with ammonia formiate. Gradient was from 0% to 95% of phase B in 10 minutes.
- Phase A Buffered (Formic acid/ammonia) aqueous solution at pH: 3.
- Phase B 50.50 mixture acetonitrile/metha ⁇ ol with ammonia formiate.
- Gradient was from 0% to 95% of phase B in 10 minutes.
- reaction mixture is stirred at 10-15 0 C for about 30m ⁇ n and then cooled to 0-5 0 C
- a solution of 20 5g (0, 135 mol) of ethyl-2-chloro-2-(hydroxy ⁇ m ⁇ no)acetate in 4OmL MeOH is added dropwise over 1 h to the reaction mixture at 0-5 0 C, the addition funnel is washed with 2mL methanol
- reaction mixture is then warmed to 20-25°C and stirred for 2h Without any isolation or purification step, 7 4g (0,148 mol) NH 2 NH 2 H 2 O are then added dropwise over 15m ⁇ n at 40°C the addition funnel is washed with 2mL of methanol and the reaction mixture is stirred at 4O 0 C for 4h then cooled to 20-25°C
- reaction mixture is stirred at 10-15 0 C for about 30m ⁇ n and then cooled to 0-5 0 C
- a solution of 166,25 g (1 ,10 mol) of ethyl-2-chloro-2-(hydroxy ⁇ m ⁇ no)acetate in 40OmL MeOH is added dropwise over 1h to the reaction mixture at 0-5 0 C 1 the addition funnel is washed with 2OmL methanol
- COMPARATIVE EXAMPLE 3 The 262,86 g of impure oil from Comparative example 2 were dissolved in 550 ml of methanol, warmed to 20-25 0 C and stirred for 2h 78,12 g (1 ,56 mol) of NH 2 NH 2 H 2 O are then added dropwise over 15m ⁇ n at 4O 0 C, the addition funnel is washed with 2OmL of methanol and the reaction mixture is stirred at 4O 0 C for 4h then cooled to 20-25 0 C
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one which process comprises the steps of: a) reacting 1 -phenylbutane-1,3-dione with ethyl 2-chloro-2-(hydroxyimino)acetate, b) subsequently reacting the product from step (a) with hydrazine or an hydrate thereof to yield 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one, wherein step (b) is carried out on the mixture resulting from step (a) without isolating ethyl 4-benzoyl-5-methylisoxazole-3-carboxylate there from.
Description
NEW PROCESS FOR PREPARING 3-METHYL-4-PHENYLISOXAZQLO r3.4-dlPYRIDAZIN-7(6H)-ONE
The present invention relates to a new process for preparing 3-methyl-4- phenylisoxazolo[3,4-d]pyridazin-7(6H)-one having the structure of formula (I):
The compound of formula (I) is a useful intermediate in the preparation of some pyridazin- 3(2H)-one derivatives which are selective inhibitors of phosphodiesterase 4 (PDE4) which have been described, for example, in the international patent applications numbers WO 03/097613 A1 , WO 2004/058729 A1 and WO 2005/049581.
These patent applications also described a two step general method for the preparation of various isoxazolo[3,4-d]pyridazin-7(6H)-one derivatives carrying substituents in the positions 3 and 4 of the isoxazolo[3,4-d]pyridazιn-7(6H)-one ring.
STEP 1
5Tl EP 2
Step 1 of the above mentioned synthetic path is also described in the article G. Renzi, V. DaI Piaz et al, Gaz. Chim. Ital. 1968, 98, 656-666 and in V. Sprio, E.Aiello et al, Ann. Chim. 1967, 57, 836-845 both of which specifically disclose the synthesis of ethyl 4- benzoyl-5-methylisoxazole-3-carboxylate (Compound III, wherein R4=methyl, R5=phenyl and R8=ethyl). The second article reports a yield of 40%.
Step 2 of the above mentioned synthetic path is also described in the article V. Sprio, E.Aiello et al, Ann. Chim. 1967, 57, 836-845 which specifically discloses the synthesis of 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (Compound IV wherein R4=methyl, and R5=phenyl). No yield is reported.
Whilst the above-mentioned two-step process is in some respects satisfactory, we have now devised an improved process allowing the manufacture of the compound of formula (I) with greater yields.
According to the present invention, there is provided a process for preparing the compound of formula (I):
which process comprises the steps of:
a) reacting 1-phenylbutane-1 ,3-dione (Ma)
with ethyl 2-chloro-2-(hydroxyιmino)acetate (Ilia)
N; XCLEt
HO
Cl
Ia)
b) subsequently reacting the product from step (a) with hydrazine or an hydrate thereof to yield 3-methyl-4-phenylιsoxazolo[3,4-d]pyridazιn-7(6H)-one (I)
wherein the process is characterised by the fact that step (b) is carried out on the mixture resulting from step (a) without isolating ethyl 4-benzoyl-5-methylιsoxazole-3-carboxylate (Via) there from.
(IVa)
Thus, contrary to the previous methods, the process of the invention proceeds by directly treating with hydrazine (or its hydrate) the reaction mixture obtained in step (a) without isolating the reaction product there from
The above described reaction process is illustrated in Figure 1.
We have found that, surprisingly, the compound of formula (I) is obtained in a greater yield by carrying out the process in the above manner (without isolation of the compound (IVa))
In an embodiment of the present invention the reactions are carried out using a C1-C3 alkanol, preferably methanol as a solvent.
In another embodiment of the present invention step a) is carried by addition of alkali alcoholate, preferably sodium methoxide followed by ethyl 2-chloro-2- (hydroxyιmino)acetate.
In still another embodiment of the present invention the molar ratio of ethyl 2-chloro-2- (hydroxyimino)acetate to 1 -phenylbutane-1 ,3-dione is comprised between 1 ,05 and 1 ,15
In still another embodiment of the present invention the molar ratio of hydrazine hydrate to 1-phenylbutane-1 ,3-dione is comprised between 1 ,15 and 1 ,25.
The reactants 1 -phenylbutane-1 ,3-dione (Ha), ethyl 2-chloro-2-(hydroxyimino)acetate (Ilia) and hydrazine hydrate used in the present invention are commercially available, for ex- ample from ABCR GmbH & CO. KG (P.O. Box 21 01 35, 76151 Karlsruhe, GERMANY), Aldrich Chemical Company, lnc (1001 West Saint Paul Avenue, Milwaukee, Wl 53233, USA) or Fluka Chemie GmbH (Industriestrasse 25, P O. Box 260, CH-9471 Buchs, SWITZERLAND).
The preferred conditions for the process of step (a) are the following:
Under an inert atmosphere, preferably under nitrogen atmosphere, 1 mol of 1- phenylbutane-1 ,3-dione is suspended in 300-350 ml of a C1 -C3 alkanol, preferably methanol, and the suspension is cooled to 10-150C. 190-200 g of MeONa 30% (methanolic solution) per mol of 1-phenylbutane-1 ,3-dione are added dropwise over 20-40 min at 10-150C and the addition funnel is washed with 10-20 ml. of methanol. The reaction mixture is stirred at 10-15°C for about 20-40 min and then cooled to 0-50C. A solution of 166,7 g (1, 1 mol) ethyl 2-chloro-2-(hydroxyimιno)acetate in 300-350 mL of methanol are added dropwise over 50-70 min to the reaction mixture at 0-50C and the addition funnel is washed with 10-20 mL of methanol.
The preferred conditions for the process of step (b) are the following:
The reaction mixture from step a) is warmed to 20-250C and stirred for 100-150 min. Then 1 ,2 mol of NH2NH2 H2O are added dropwise over 10-20 min at 35-45°C, the addition funnel is washed with 10-20 ml_ MeOH and the reaction mixture is stirred at 35-450C for
220-260 min then cooled to 20-250C. Finally 480-500 mL of water are added and the reaction mixture is stirred for 50-70 min at 20-250C then 20-40 min at 0-50C. The product is isolated by filtration then washed with 2x320 mL of cold MeOH/H2O 1:1 and vacuum dried at 40-450C overnight.
The method of synthesis described in the present invention will be further illustrated by the following examples. The examples are given by the way of illustration only and are not to be construed as limiting.
The structures of the prepared compounds were confirmed by 1H-NMR and MS. NMR were recorded using a Varian Gemini-200 NMR spectrometer operating at frequency of 200 or 300 MHz. Tetramethyl silane was used as a reference and samples were solved in deuterated dimethylsulphoxide (DMSO-d6) or deuterated chloroform (CDCI3).
Their purity was determined by HPLC, in Alliance 2795 Waters instrument equipped with diode array detector (DAD) and ZMD or ZQ mass detector (electrospray ionization). HPLC method used a Symmetry C18 column (3.5 μm, 21x100 mm) and mobile phase was composed by two phases: Phase A: Buffered (Formic acid/ammonia) aqueous solution at pH: 3. Phase B: 50.50 mixture acetonitrile/methaπol with ammonia formiate. Gradient was from 0% to 95% of phase B in 10 minutes.
Preparative HPLC-MS experiments were performed on a Gilson instrument equipped with a binary pump (Gilson piston pump 321); a vacuum degasser (Gilson 864); an injector- fraction collector (Gilson liquid handler 215); two injection modules, analytical and preparative (Gilson 819); a valve (Gilson Valvemate 7000); a 1/1000 splitter (Acurate by LC Packings); a make-up pump (Gilson 307); a diode array detector (Gilson 170) and a MS detector (a Thermoquest Finnigan aQa, a quadrupole mass spectrometer with ES and APCI ionisation modes). The HPLC-MS instrument was controlled by an IBM PC.
EXAMPLES
EXAMPLE 1
2Og (0,123 mol) of 1-phenylbutane-1 ,3-dιone and 4OmL methanol are introduced under nitrogen atmosphere, into a four-necked flask fitted with mechanical stirrer and addition funnel and the suspension is cooled down to 10-150C 24 4g of a 30% solution of sodium methoxide in methanol are added dropwise over 30mιn at 10-150C The addition funnel is washed with 2mL of methanol
The reaction mixture is stirred at 10-150C for about 30mιn and then cooled to 0-50C A solution of 20 5g (0, 135 mol) of ethyl-2-chloro-2-(hydroxyιmιno)acetate in 4OmL MeOH is added dropwise over 1 h to the reaction mixture at 0-50C, the addition funnel is washed with 2mL methanol
The reaction mixture is then warmed to 20-25°C and stirred for 2h Without any isolation or purification step, 7 4g (0,148 mol) NH2NH2 H2O are then added dropwise over 15mιn at 40°C the addition funnel is washed with 2mL of methanol and the reaction mixture is stirred at 4O0C for 4h then cooled to 20-25°C
Finally 6OmL of water are added and the reaction mixture is stirred for 1 h at 20-250C then 30mιn at 0-50C
The resulting mixture is filtered, the resulting solid is washed with 2x40mL cold MeOH/H2O 1 1 and vacuum dried at 40°C overnight Yielding 22,5 g (0,099 mol) of 3- methyl-4-phenylιsoxazolo[3,4-d]pyrιdazιn-7(6H)-one (yield = 80,5%)
COMPARATIVE EXAMPLE 2
162,19 g of 1-phenylbutane-1 ,3-dιone (1 mol) are introduced under nitrogen atmosphere, into a four-necked flask fitted with mechanical stirrer and addition funnel and the suspension is cooled down to 10-150C 198 g of a 30% sodium methoxide / methanolic solution are added dropwise over 30mιn at 10-150C The addition funnel is washed with 2mL of methanol
The reaction mixture is stirred at 10-150C for about 30mιn and then cooled to 0-50C A solution of 166,25 g (1 ,10 mol) of ethyl-2-chloro-2-(hydroxyιmιno)acetate in 40OmL MeOH
is added dropwise over 1h to the reaction mixture at 0-50C1 the addition funnel is washed with 2OmL methanol
The final mixture was stirred at room temperature overnight The crude was worked up and 262,86 g of an oil were isolated The content of ethyl 4-benzoyl-5-methylιsoxazole-3- carboxylate in the oil was determined to be 86% by CG-EI This represents a yield of 87,1% (expressed as pure product)
COMPARATIVE EXAMPLE 3 The 262,86 g of impure oil from Comparative example 2 were dissolved in 550 ml of methanol, warmed to 20-250C and stirred for 2h 78,12 g (1 ,56 mol) of NH2NH2 H2O are then added dropwise over 15mιn at 4O0C, the addition funnel is washed with 2OmL of methanol and the reaction mixture is stirred at 4O0C for 4h then cooled to 20-250C
Finally 48OmL of water are added and the reaction mixture is stirred for 1h at 20-250C then 30mιπ at 0-50C
The resulting mixture is filtered, the resulting solid is washed with 2x40mL cold MeOH/H2O 1 1 and vacuum dried at 40°C overnight Yielding 168,2 g (0,740 mol) of 3- methyl-4-phenylιsoxazolo[3,4-d]pyrιdazιn-7(6H)-one (yield = 84,9%) HPLC-MS(+/-)= 228 MS-FIA= 228
After cooling with an ice bath, a precipitate was formed and collected by filtration and washed with some pre-cooled alcoholic solvents
The combined yield of comparative examples 2 and 3 representing the yield of manufacturing 3-methyl-4-phenylιsoxazolo[3,4-d]pyπdazιn-7(6H)-one in a two step reacting with isolation of the intermediate ethyl 4-benzoyl-5-methylιsoxazole-3-carboxylate is 74,0% (87,1 % X 84,9%)
This yield is significantly lower that the yield obtained when the manufacturing process when it is carried out in the form of a one-pot reaction as claimed in the present invention and exemplified in Example 1
Claims
1 A process for preparing 3-methyl-4-phenylιsoxazolo[3,4-dJpyrιdazιn-7(6H)-one which process comprises the steps of
a) reacting 1-phenylbutane-1 ,3-dιone with ethyl 2-chloro-2-(hydroxyιmιno)acetate
b) subsequently reacting the product from step (a) with hydrazine or an hydrate thereof to yield 3-methyl-4-phenylιsoxazolo[3,4-d]pyπdazιn-7(6H)-one
wherein the process is characterised by the fact that step (b) is carried out on the mixture resulting from step (a) without isolating ethyl 4-beπzoyl-5-methylιsoxazole- 3-carboxylate there from
2 A process according to claim 1 characterized in that the reactions are carried out using a C1 -C3 alkanol as a solvent
3 A process according to claim 2 characterized in that the alkanol is methanol
4 A process according to any preceding claim characterized in that step a) is carried by addition of alkali alcoholate followed by ethyl 2-chloro-2-(hydroxyιmιno)acetate
5 A process according to claim 4 wherein the alkali alcoholate is sodium methoxide
6 A process according to any preceding claim wherein the molar ratio of ethyl 2- chloro-2-(hydroxyιmιπo)acetate to 1-phenylbutane-1 ,3-dιone is comprised between 1 ,05 and 1 ,15
7 A process according to any preceding claim wherein the molar ratio of hydrazine hydrate to 1 -phenylbutane-1 ,3-dιone is comprised between 1 ,15 and 1 ,25
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE602008004742T DE602008004742D1 (en) | 2007-03-02 | 2008-02-13 | NEW METHOD FOR THE PREPARATION OF 3-METHYL-4-PHENYL ISOXAZOLOE3,4-DIPROIDAZINE-7 (6H) -ONE |
| AT08707692T ATE496923T1 (en) | 2007-03-02 | 2008-02-13 | NEW PROCESS FOR THE PREPARATION OF 3-METHYL-4-PHENYLISOXAZOLOÄ3,4-DÜPYRIDAZINE-7(6H)-ONE |
| JP2009551112A JP2010520158A (en) | 2007-03-02 | 2008-02-13 | Novel process for the preparation of 3-methyl-4-phenylisoxazolo [3,4-d] pyridazin-7 (6H) -one |
| CA002679619A CA2679619A1 (en) | 2007-03-02 | 2008-02-13 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6h)-one |
| BRPI0807273-6A2A BRPI0807273A2 (en) | 2007-03-02 | 2008-02-13 | "PROCESS FOR PREPARING 3-METHYL-4-PHENYLISOXAZOLE [3,4-D] PYRIDAZIN -7 (6H) -ON" |
| EP08707692A EP2125830B1 (en) | 2007-03-02 | 2008-02-13 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6h)-one |
| CN200880005978A CN101679453A (en) | 2007-03-02 | 2008-02-13 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one |
| NZ578671A NZ578671A (en) | 2007-03-02 | 2008-02-13 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6h)-one |
| AU2008224206A AU2008224206A1 (en) | 2007-03-02 | 2008-02-13 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one |
| US12/529,511 US20100137591A1 (en) | 2007-03-02 | 2008-02-13 | Process for preparing 3-methyl-4-phenylisoxazolo [3,4-d]pyridazin-7(6h)-one |
| MX2009009232A MX2009009232A (en) | 2007-03-02 | 2008-02-13 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyrida zin-7(6h)-one. |
| IL200166A IL200166A0 (en) | 2007-03-02 | 2009-07-30 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6h)-one |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200700564A ES2320954B1 (en) | 2007-03-02 | 2007-03-02 | NEW PREPARATION PROCEDURE FOR 3-METHYL-4-PHENYLISOXAZOLO (3,4-D) IRIDAZIN-7 (6H) -ONA. |
| ESP200700564 | 2007-03-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008107064A1 true WO2008107064A1 (en) | 2008-09-12 |
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ID=38617235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2008/001080 WO2008107064A1 (en) | 2007-03-02 | 2008-02-13 | New process for preparing 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6h)-one |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US20100137591A1 (en) |
| EP (1) | EP2125830B1 (en) |
| JP (1) | JP2010520158A (en) |
| KR (1) | KR20090116753A (en) |
| CN (1) | CN101679453A (en) |
| AR (1) | AR065511A1 (en) |
| AT (1) | ATE496923T1 (en) |
| AU (1) | AU2008224206A1 (en) |
| BR (1) | BRPI0807273A2 (en) |
| CA (1) | CA2679619A1 (en) |
| CL (1) | CL2008000598A1 (en) |
| DE (1) | DE602008004742D1 (en) |
| EC (1) | ECSP099558A (en) |
| ES (1) | ES2320954B1 (en) |
| IL (1) | IL200166A0 (en) |
| MX (1) | MX2009009232A (en) |
| NZ (1) | NZ578671A (en) |
| PE (1) | PE20081793A1 (en) |
| RU (1) | RU2009136314A (en) |
| TW (1) | TW200844105A (en) |
| UY (1) | UY30913A1 (en) |
| WO (1) | WO2008107064A1 (en) |
| ZA (1) | ZA200905193B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7960383B2 (en) | 2004-06-18 | 2011-06-14 | Laboratorios Almirall Sa | Pyridazin-3(2H)-one derivatives and their use as PDE4 inhibitors |
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| ES2211344B1 (en) * | 2002-12-26 | 2005-10-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
| ES2251867B1 (en) * | 2004-06-21 | 2007-06-16 | Laboratorios Almirall S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
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| US5679696A (en) * | 1992-07-28 | 1997-10-21 | Rhone-Poulenc Rorer Limited | Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group |
| DE19533975A1 (en) * | 1995-09-14 | 1997-03-20 | Merck Patent Gmbh | Arylalkyl diazinones |
| DE19540475A1 (en) * | 1995-10-20 | 1997-04-24 | Schering Ag | Chiral methylphenyloxazolidinones |
| PL329922A1 (en) * | 1996-05-20 | 1999-04-26 | Darwin Discovery Ltd | Quinoline carboxamides as inhibitors of the tumour necrosis factor and of phosphodiesterase |
| RU2162467C2 (en) * | 1996-05-20 | 2001-01-27 | Дарвин Дискавери Лимитед | Benzofuran carboxamides and pharmaceutical composition containing thereof |
| AU751453C (en) * | 1997-11-25 | 2003-04-10 | Warner-Lambert Company | Benzenesulfonamide inhibitors of PDE-IV and their therapeutic use |
| WO2000050402A1 (en) * | 1999-02-25 | 2000-08-31 | Merck Frosst Canada & Co. | Pde iv inhibiting compounds, compositions and methods of treatment |
| US6699890B2 (en) * | 2000-12-22 | 2004-03-02 | Memory Pharmaceuticals Corp. | Phosphodiesterase 4 inhibitors |
| CN1604776A (en) * | 2001-10-16 | 2005-04-06 | 记忆药物公司 | 4-4-alkoxy-3-hydroxyphenyl-2-pyrrolidone derivatives as pde-4 inhibitors for the treatment of neurological syndromes |
| AR037517A1 (en) * | 2001-11-05 | 2004-11-17 | Novartis Ag | DERIVATIVES OF NAFTIRIDINES, A PROCESS FOR THE PREPARATION, PHARMACEUTICAL COMPOSITION AND THE USE OF THEM FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF AN INFLAMMATORY DISEASE |
| ES2195785B1 (en) * | 2002-05-16 | 2005-03-16 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
| CN100513397C (en) * | 2002-11-19 | 2009-07-15 | 记忆药物公司 | Pyridine n-oxide compounds as phosphodiesterase 4 inhibitors |
| ES2211344B1 (en) * | 2002-12-26 | 2005-10-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
| RU2379292C2 (en) * | 2003-04-18 | 2010-01-20 | Мемори Фармасьютиклз Корпорейшн | Pyrazole derivatives as phosphodiesterase 4 inhibitors |
| ES2232306B1 (en) * | 2003-11-10 | 2006-08-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
| ES2251866B1 (en) * | 2004-06-18 | 2007-06-16 | Laboratorios Almirall S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
| ES2251867B1 (en) * | 2004-06-21 | 2007-06-16 | Laboratorios Almirall S.A. | NEW DERIVATIVES OF PIRIDAZIN-3 (2H) -ONA. |
| EP2222639A1 (en) * | 2007-11-21 | 2010-09-01 | Decode Genetics EHF | Biaryl pde4 inhibitors for treating pulmonary and cardiovascular disorders |
-
2007
- 2007-03-02 ES ES200700564A patent/ES2320954B1/en not_active Withdrawn - After Issue
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2008
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- 2008-02-13 DE DE602008004742T patent/DE602008004742D1/en active Active
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- 2008-02-13 CN CN200880005978A patent/CN101679453A/en active Pending
- 2008-02-13 KR KR1020097017603A patent/KR20090116753A/en not_active Application Discontinuation
- 2008-02-13 MX MX2009009232A patent/MX2009009232A/en unknown
- 2008-02-13 WO PCT/EP2008/001080 patent/WO2008107064A1/en active Application Filing
- 2008-02-13 CA CA002679619A patent/CA2679619A1/en not_active Abandoned
- 2008-02-13 AU AU2008224206A patent/AU2008224206A1/en not_active Abandoned
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- 2008-02-13 EP EP08707692A patent/EP2125830B1/en active Active
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- 2008-02-28 AR ARP080100823A patent/AR065511A1/en not_active Application Discontinuation
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2009
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- 2009-07-30 IL IL200166A patent/IL200166A0/en unknown
- 2009-08-04 EC EC2009009558A patent/ECSP099558A/en unknown
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| SPRIO, VINCENZO ET AL: "Nitrogen heterocycles. II. Hydrogenation of isoxazolo[3,4- d]pyridazin-7-ones, isoxazolo[3,4-d]pyridazin-4-ones, and isoxazolo[3,4-d]pyridazine-4,7-diones", ANNALI DI CHIMICA (ROME, ITALY), vol. 57, no. 7, 1967, pages 836 - 845, XP008085372 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7960383B2 (en) | 2004-06-18 | 2011-06-14 | Laboratorios Almirall Sa | Pyridazin-3(2H)-one derivatives and their use as PDE4 inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2010520158A (en) | 2010-06-10 |
| US20100137591A1 (en) | 2010-06-03 |
| KR20090116753A (en) | 2009-11-11 |
| UY30913A1 (en) | 2008-07-31 |
| ES2320954A1 (en) | 2009-05-29 |
| AR065511A1 (en) | 2009-06-10 |
| NZ578671A (en) | 2011-04-29 |
| ATE496923T1 (en) | 2011-02-15 |
| IL200166A0 (en) | 2010-04-15 |
| EP2125830B1 (en) | 2011-01-26 |
| ZA200905193B (en) | 2010-05-26 |
| ES2320954B1 (en) | 2010-03-16 |
| CA2679619A1 (en) | 2008-09-12 |
| EP2125830A1 (en) | 2009-12-02 |
| MX2009009232A (en) | 2009-10-12 |
| ECSP099558A (en) | 2009-09-29 |
| CN101679453A (en) | 2010-03-24 |
| BRPI0807273A2 (en) | 2014-04-29 |
| CL2008000598A1 (en) | 2008-09-05 |
| TW200844105A (en) | 2008-11-16 |
| DE602008004742D1 (en) | 2011-03-10 |
| AU2008224206A1 (en) | 2008-09-12 |
| RU2009136314A (en) | 2011-04-10 |
| PE20081793A1 (en) | 2008-12-18 |
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