CN118388413A - Method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone - Google Patents
Method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 44
- -1 4-amino-2, 6-dichlorophenoxy Chemical group 0.000 title claims abstract description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 239000003513 alkali Substances 0.000 claims abstract description 37
- 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 claims abstract description 21
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000003999 initiator Substances 0.000 claims abstract description 11
- 150000003254 radicals Chemical class 0.000 claims abstract description 11
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000009471 action Effects 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 110
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 15
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000004537 pulping Methods 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical group [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 10
- PFQNEKHHAFIRRV-UHFFFAOYSA-N 3-(4-amino-2,6-dichlorophenoxy)-5-propan-2-yl-1h-pyridazin-6-one Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(N)=CC=2Cl)Cl)=N1 PFQNEKHHAFIRRV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229910001867 inorganic solvent Inorganic materials 0.000 claims description 2
- 239000003049 inorganic solvent Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 229920001021 polysulfide Polymers 0.000 claims description 2
- 239000005077 polysulfide Substances 0.000 claims description 2
- 150000008117 polysulfides Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical group [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- UZNGRHDUJIVHQT-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].C[C-]=C UZNGRHDUJIVHQT-UHFFFAOYSA-M 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 11
- 239000012265 solid product Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 4
- 229940121486 resmetirom Drugs 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- GUSWJGOYDXFJSI-UHFFFAOYSA-N 3,6-dichloropyridazine Chemical compound ClC1=CC=C(Cl)N=N1 GUSWJGOYDXFJSI-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone, belonging to the field of pharmacy. The method comprises the following steps: (1) The compound V and the compound IV react under the action of a catalyst, acid and a free radical initiator to obtain a compound III; (2) reacting the compound III with alkali to obtain a compound II; (3) The compound II reacts with alkali to obtain the compound I, namely 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone. Compared with the method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone by using isopropenyl magnesium bromide in the prior art, the method has simpler operation process, and the used materials are cheap and easy to obtain, thus being suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone.
Background
Resmetirom (MGL-3196, chinese name: ruisentharo) is an oral small molecule agonist targeting the THR-beta receptor, developed by Madrigal Pharmaceuticals company. Month 12 of 2022, madrigal announced that MGL-3196 reached two major endpoints in the critical three-phase MAESTRO-NASH clinical trial for the treatment of NASH (non-alcoholic steatohepatitis). Among the results for the second and third phases, MGL-3196 is expected to be the NASH therapeutic drug approved by the FDA for the fastest market, and thus has received wide attention from both industry and investors. Resmetirom has a molecular weight of 435.22, a molecular formula of C 17H12Cl2N6O4, and a structural formula as follows:
The key intermediate for the current synthesis Resmetirom is 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one, CAS number: 920509-28-0, molecular weight 314.166, molecular formula C 13H13Cl2N3O2, its structural formula is as follows:
There are few commercial suppliers of 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one and the reported synthetic routes have certain drawbacks, which severely limit future Resmetirom commercial production.
Patent CN105008335A reports the following synthetic route: 3, 6-dichloropyridazine is taken as a starting material to carry out substitution reaction to obtain a compound 3, then benzoic anhydride carries out hydrolysis reaction on a Bz protecting group (benzoyl) on the amino group of the compound 3 to generate a compound 4, and then a chlorine atom on a pyridazine ring to generate a compound 5. And (3) carrying out conjugate addition on carbon-carbon double bonds on the pyridazine ring by isopropenyl magnesium bromide to generate a key compound 6, and finally, under the condition of strong alkali, migrating the isopropenyl double bonds and simultaneously removing Bz protecting groups to finally obtain a product 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazine-3 (2H) -ketone. The key to this route is the isopropyl group on the pyridazine ring by conjugate addition via isopropenylmagnesium bromide followed by isomerization. However, this method has the following problems: (1) The reaction conditions are strict, anhydrous and anaerobic are required, and anhydrous tetrahydrofuran is also required as a reaction solvent; (2) the raw material isopropenyl magnesium bromide is expensive. These problems increase the risk and cost of the amplification process, which is detrimental to future industrial scale-up.
Therefore, development of a novel method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone, which has relatively simple synthesis process, high reaction selectivity and low-cost and easily available raw materials, is urgently needed.
Disclosure of Invention
The invention aims to provide a novel method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazine-3 (2H) -ketone, which has the advantages of simpler synthetic route, higher reaction selectivity and easily available raw materials and is suitable for industrial production.
The invention provides a method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone, which comprises the following steps:
(1) The compound V and the compound IV react under the action of a catalyst, acid and a free radical initiator to obtain a compound III;
(2) Reacting the compound III with alkali to obtain a compound II;
(3) The compound II reacts with alkali to obtain the compound I, namely 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone.
Further, in the step (1), the feeding mode of the reaction is as follows: firstly, mixing a compound V, a compound IV, a catalyst and acid in a solvent for reaction, and then adding a solution of a free radical initiator; the mol ratio of the compound V to the compound IV to the catalyst to the acid to the free radical initiator is 1 (0.95-1.1): 0.1-0.2): 2-3; the acid is an organic acid, the free radical initiator is a polysulfide, and the catalyst is silver salt; the solvent of the reaction is an inorganic solvent; the reaction temperature is 65-85 ℃ and the reaction time is 0.5-3 hours;
And/or in the step (2), the molar ratio of the compound III to the alkali is 1 (3-4); the alkali is an organic alkali; the solvent of the reaction is an organic solvent; the temperature of the reaction is 90-110 ℃ and the time is 20-30 hours;
And/or, in the step (3), the molar ratio of the compound II to the alkali is 1 (9-11); the alkali is inorganic alkali; the solvent for the reaction is a mixture of an organic solvent and water; the reaction temperature is 110-130 ℃ and the reaction time is 10-14 hours.
Further, in the step (1), the molar ratio of the compound V, the compound IV, the catalyst, the acid and the free radical initiator is 1:1.05:0.1:0.2:2; the acid is trifluoroacetic acid, the persulfate is persulfate, preferably ammonium persulfate, and the catalyst is silver nitrate; the solvent of the reaction is water; the temperature of the reaction is 70 ℃ and the time is 1-2 hours;
and/or in step (2), the molar ratio of compound III to base is 1:3.5; the alkali is sodium acetate; the solvent of the reaction is acetic acid; the temperature of the reaction is 100 ℃ and the time is 24 hours;
In the step (3), the molar ratio of the compound II to the alkali is 1:10; the alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide; the organic solvent is methanol; the temperature of the reaction was 120℃for 12 hours.
Further, after the reaction in the step (1) is finished, the method further comprises the following purification steps: cooling the reaction solution to 0 ℃, adding alkali to adjust the pH to be=9, extracting by ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove ethyl acetate, pulping and purifying a crude product by using a mixed solution of n-heptane and ethyl acetate, and drying to obtain a compound III;
And/or, after the reaction in the step (2) is finished, the method further comprises the following purification steps: adding water into the reaction solution, and crystallizing; filtering, pulping and purifying a filter cake by using water, and drying the obtained crude product by using a mixed solution of n-heptane and ethyl acetate to obtain a compound II;
And/or, after the reaction in the step (3) is finished, the method further comprises the following purification steps: the reaction solution is concentrated under reduced pressure to remove the solvent, water is added to separate out the crude product, and the crude product is filtered, pulped and purified by methyl tertiary butyl ether and dried to obtain the compound I.
Further, in the step (1), the feeding mode of the reaction is as follows: compound v, compound iv, trifluoroacetic acid and silver nitrate were added to water, followed by ammonium persulfate.
Further, the preparation method of the compound V comprises the following steps:
And (3) reacting the compound VII with the compound VI under the action of alkali to obtain a compound V.
Further, the molar ratio of the compound VII, the compound VI and the base is 1: (2.5-3.5): (3.0-5.0), wherein the base is an organic base; the solvent of the reaction is an organic solvent; the reaction temperature is 0-35 ℃ and the reaction time is more than 6 hours.
Further, the molar ratio of the compound VII, the compound VI and the base is 1:3:4.5, wherein the base is triethylamine or N, N-diisopropylethylamine; the solvent of the reaction is dichloromethane; the reaction temperature is 0-25 ℃ and the reaction time is 8-10 hours.
Further, in the preparation method of the compound V, after the reaction is finished, the method further comprises the following purification steps: adding saturated sodium bicarbonate aqueous solution into the reaction solution, extracting and separating the solution, extracting the water phase by ethyl acetate, combining the organic phases, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, pulping and purifying the obtained crude product by using a mixed solution of n-heptane and ethyl acetate, and drying to obtain the compound V.
Further, the preparation method of the compound VII comprises the following steps:
The compound IX and the compound VIII react under the action of alkali to obtain the compound VII.
Further, the molar ratio of compound IX, compound viii and base is 1: (0.9-1.1): (1.1-1.2), wherein the alkali is an inorganic alkali, and the solvent for the reaction is an organic solvent; the reaction temperature is 60-120 ℃ and the reaction time is more than 19 hours.
Further, the molar ratio of compound IX, compound viii and base is 1:1.02:1.15, wherein the base is potassium carbonate, cesium carbonate or sodium carbonate, and the solvent for the reaction is N, N-dimethylacetamide, N-dimethylformamide or dimethyl sulfoxide; the reaction temperature is 70-110 ℃ and the reaction time is more than 19 hours.
Further, in the preparation method of the compound VII, after the reaction is finished, the method further comprises the following purification steps: adding water into the reaction solution, crystallizing at 0 ℃, precipitating solid, filtering, washing a filter cake with water, pulping and purifying with a mixed solution of n-heptane and ethyl acetate, and drying to obtain a compound VII.
In conclusion, the synthesis route for preparing the 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazine-3 (2H) -ketone is simpler, the reaction selectivity is higher, the raw materials are easy to obtain, and the method is suitable for industrial production.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1: nuclear magnetic spectrum of compound i.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The preparation of 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one was carried out according to the following synthetic route:
EXAMPLE 1 method for Synthesis of 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one
1. Preparation of Compound VII
Compound IX (200 g,1.344 mol), compound VIII (244 g,1.371 mol) and cesium carbonate (504 g,1.545 mol) were dissolved in N, N-dimethylacetamide (1L), heated to 110℃for 3 hours, and then cooled to 70℃for further 16 hours. The reaction was monitored by TLC and the starting material was essentially complete. Cooling the reaction solution to below 20 ℃, adding 4L of water, crystallizing at 0 ℃, precipitating a large amount of solids, filtering, washing a filter cake with water, pulping and purifying the filter cake with n-heptane/ethyl acetate (3/1), and vacuum drying the obtained solid product at 50 ℃ for 48 hours to obtain 351g of compound VII as a yellow solid with a molar yield of 90%; HPLC purity 98.1%; MS (ESI +)m/z 290.1[M+H]+).
2. Synthesis of Compound V
Compound VII (300 g,1.032 mol) and triethylamine (470 g, 4.640 mol) were dissolved in 2.1L of methylene chloride to prepare a reaction solution, and Compound VI (243 g,3.096 mol) was dissolved in methylene chloride (0.9L). After the reaction solution is cooled to 0 ℃, dropwise adding a dichloromethane solution of the compound VI into the reaction solution, naturally heating the reaction solution to room temperature after the dropwise adding is finished, and continuously reacting for 8 hours, wherein a large amount of triethylamine hydrochloride precipitate is generated in the reaction system. The reaction was monitored by TLC and the starting material was essentially complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution until the reaction solution was clear, the separated solution was extracted, the aqueous phase was extracted twice more with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase is filtered, the organic solvent is removed by reduced pressure rotary evaporation at 45 ℃, the crude product is pulped and purified by n-heptane/ethyl acetate (1/1), the obtained solid product is dried in vacuum at 45 ℃ for 12 hours, 326g of compound V is obtained as off-white solid, and the molar yield is 95%; HPLC purity 98.7%; MS (ESI +)m/z 332.0[M+H]+).
3. Synthesis of Compound III
Compound V (243 g,0.732 mol), isobutyric acid (68 g,0.769 mol), trifluoroacetic acid (16.6 g,0.146 mol) and silver nitrate (12.3 g,0.0732 mol) were added to 1.5L of water, and in addition, ammonium persulfate (334 g, 1.460 mol) was dissolved in 1L of water to prepare a solution. After the temperature of the reaction solution is raised to 60 ℃, dropwise adding an ammonium persulfate aqueous solution into the reaction solution, wherein the dropwise adding process can release heat, the temperature of the reaction solution is controlled to be 70-85 ℃ during dropwise adding, the reaction is continued for 1-2 hours at 70 ℃ after the dropwise adding is finished, and the reaction progress is monitored by TLC and HPLC. After the reaction, the reaction solution was cooled to 0 ℃, and sodium bicarbonate powder was slowly added in a plurality of batches to generate a large amount of carbon dioxide gas, and ph=9 was adjusted. After three extractions with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation at 45 ℃. The crude product was purified by beating with n-heptane/ethyl acetate (1/1), and the resulting solid product was dried under vacuum at 45℃for 12 hours to give 244g of compound III as an off-white solid in 89% molar yield; HPLC purity 97.3%; MS (ESI +)m/z374.2[M+H]+).
4. Synthesis of Compound II
Compound iii (200 g, 0.53mol) and sodium acetate (153.6 g,1.872 mol) were added to 1L acetic acid and reacted at 100 ℃ for 24 hours, and the progress of the reaction was monitored by TLC and HPLC. After the reaction is finished, the temperature is reduced to 75 ℃, and water is slowly added into the reaction liquid for crystallization. Cooling to room temperature, filtering, washing a filter cake with a small amount of water, pulping and purifying a crude product by n-heptane/ethyl acetate (1/1), and vacuum drying the obtained solid product at 45 ℃ for 24 hours to obtain 162g of a compound II, an off-white solid, and a molar yield of 85%; HPLC purity 98.6%; MS (ESI +)m/z356.1[M+H]+).
5. Synthesis of Compound I
An aqueous solution (300 mL) of compound II (150 g, 0.425 mol) and sodium hydroxide (169 g,4.255 mol) was added to methanol (300 mL), and the reaction was carried out at 120℃for 12 hours, and the progress of the reaction was monitored by TLC and HPLC. After the reaction is finished, cooling to room temperature, removing methanol by rotary evaporation under reduced pressure, adding water into the reaction liquid to precipitate a crude product, filtering the crude product, pulping and purifying by methyl tertiary butyl ether, and vacuum drying the obtained solid product at 45 ℃ for 24 hours to obtain 127g of compound I, namely 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone, white solid, wherein the molar yield is 96%; HPLC purity 99.3%; MS (ESI +)m/z 314.2[M+H]+;
1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.27(s,1H),6.66(s,2H),5.65(s,2H),3.09–2.94(m,1H),1.16(d,J＝6.9Hz,6H). The nuclear magnetic spectrum 1 specifically shows the nuclear magnetic spectrum of the compound I.
In summary, the overall yield of 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one synthesized in this example was 62.1%.
Example 2 scaled-up production
1. Preparation of Compound VII
Compound IX (5 kg,33.6 mol), compound VIII (6.1 kg,34.3 mol) and cesium carbonate (12.6 kg,38.64 mol) were dissolved in N, N-dimethylacetamide (25L), heated to 110℃for 3 hours, and then cooled to 70℃for further 16 hours. The reaction was monitored by TLC and the starting material was essentially complete. Cooling the reaction solution to below 20 ℃, adding 100L of water for crystallization at 0 ℃, precipitating a large amount of solids, filtering, washing a filter cake with water, pulping and purifying the filter cake with n-heptane/ethyl acetate (3/1), and vacuum drying the obtained solid product at 50 ℃ for 48 hours to obtain 8.9kg of compound VII, yellow solid with a molar yield of 92%; HPLC purity 98.5%; MS (ESI +)m/z 290.1[M+H]+).
2. Synthesis of Compound V
Compound VII (8 kg,27.52 mol) and triethylamine (12.5 kg,123.8 mol) were dissolved in 56L of methylene chloride to prepare a reaction solution, and Compound VI (6.5 kg,82.6 mol) was dissolved in 24L of methylene chloride. After the reaction solution is cooled to 0 ℃, dropwise adding a dichloromethane solution of the compound VI into the reaction solution, naturally heating the reaction solution to room temperature after the dropwise adding is finished, and continuously reacting for 8 hours, wherein a large amount of triethylamine hydrochloride precipitate is generated in the reaction system. The reaction was monitored by TLC and the starting material was essentially complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution until the reaction solution was clear, the separated solution was extracted, the aqueous phase was extracted twice more with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase is filtered, the organic solvent is removed by reduced pressure rotary evaporation at 45 ℃, the crude product is pulped and purified by n-heptane/ethyl acetate 1/1, the obtained solid product is dried in vacuum at 45 ℃ for 12 hours, 8.78kg of compound V is obtained as an off-white solid, and the molar yield is 96.1%; HPLC purity 98.7%; MS (ESI +)m/z 332.0[M+H]+).
3. Synthesis of Compound III
Compound V (7 kg,21.2 mol), isobutyric acid (2.0 kg,22.26 mol), trifluoroacetic acid (412 g,4.24 mol) and silver nitrate (360 g,2.12 mol) were added to 42L of water, and ammonium persulfate (9.7 kg,42.4 mol) was dissolved in 28L of water to prepare a solution. After the temperature of the reaction solution is raised to 60 ℃, dropwise adding an ammonium persulfate aqueous solution into the reaction solution, wherein the dropwise adding process can release heat, the temperature of the reaction solution is controlled to be 70-85 ℃ during dropwise adding, the reaction is continued for 1-2 hours at 70 ℃ after the dropwise adding is finished, and the reaction progress is monitored by TLC and HPLC. After the reaction, the reaction solution was cooled to 0 ℃, and sodium bicarbonate powder was slowly added in a plurality of batches to generate a large amount of carbon dioxide gas, and ph=9 was adjusted. After three extractions with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation at 45 ℃. The crude product was purified by beating with n-heptane/ethyl acetate 1/1 and the resulting solid product was dried under vacuum at 45℃for 12 hours to give 7.15kg of compound III as an off-white solid in a molar yield of 90%; HPLC purity 97.2%; MS (ESI +)m/z 374.2[M+H]+).
4. Synthesis of Compound II
Compound III (6 kg,16.1 mol) and sodium acetate (4.6 kg,56.4 mol) were added to 30L of acetic acid and reacted at 100℃for 24 hours, and the progress of the reaction was monitored by TLC and HPLC. After the reaction is finished, the temperature is reduced to 75 ℃, and water is slowly added into the reaction liquid for crystallization. Cooling to room temperature, filtering, washing a filter cake with a small amount of water, pulping and purifying a crude product by n-heptane/ethyl acetate (1/1), and vacuum drying the obtained solid product at 45 ℃ for 24 hours to obtain 4.9kg of a compound II, an off-white solid, wherein the molar yield is 86%; HPLC purity 98.8%; MS (ESI +)m/z356.1[M+H]+).
5. Synthesis of Compound I
An aqueous solution (9L) of compound II (4.5 kg,12.6 mol) and sodium hydroxide (5 kg,126 mol) was added to methanol (9L) and reacted at 120℃for 12 hours, and the progress of the reaction was monitored by TLC and HPLC. After the reaction is finished, cooling to room temperature, removing methanol by rotary evaporation under reduced pressure, adding water into the reaction liquid to precipitate a crude product, filtering the crude product, pulping and purifying by methyl tertiary butyl ether, and vacuum drying the obtained solid product at 45 ℃ for 24 hours to obtain 3.84kg of compound I, namely 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone, which is a white solid with a molar yield of 97%; HPLC purity 99.7%; ; MS (ESI +)m/z 314.2[M+H]+).
1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.27(s,1H),6.66(s,2H),5.65(s,2H),3.09–2.94(m,1H),1.16(d,J＝6.9Hz,6H).
In summary, the overall yield of 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one synthesized in this example was 65.9%.
The following experiments prove the beneficial effects of the invention.
Experimental example 1, step 1 screening experiment
Referring to the procedure of step 1 of example 1, the compound VII was prepared with only the difference that the amount of the compound of formula VIII, the kind and amount of the base were controlled according to Table 1. The molar yields and purities of compound VII are shown in Table 1.
TABLE 1 molar yields and purities of the compounds VII obtained under different reaction conditions
As can be seen from Table 1, when the amount of the compound of formula VIII is 1.02eq. And the amount of cesium carbonate is 1.15eq. The molar yield and purity of the compound VII obtained are highest.
Experimental example 2, step 2 screening experiment
Referring to the procedure of step 2 of example 1, compound V was prepared only by controlling the amount of the compound of formula VI and the amount of triethylamine according to Table 2. The molar yield and purity of compound V are shown in table 2.
TABLE 2 molar yield and purity of the resulting Compound V under different reaction conditions
| Step 2 | The amount of the compound of formula VI | Triethylamine amount | Molar yield | Purity of |
| Example 1 | 3.0eq. | 4.5eq. | 95％ | 98.7％ |
| Comparative experiment group 5 | 2.5eq. | 4.5eq. | 89％ | 94.3％ |
| Comparative experiment group 6 | 2eq. | 4.5eq. | 72％ | 94.6％ |
| Comparative experiment group 7 | 3eq. | 3eq. | 89％ | 86.7％ |
| Comparative experiment group 8 | 3eq. | 5eq. | 81％ | 89.5％ |
As can be seen from Table 2, when the amount of the compound of formula VI was 3.0eq. And the amount of triethylamine was 4.5eq. The molar yield and purity of the obtained compound V were highest.
Experimental example 3, step 3 screening experiment
Referring to the procedure of step 3 of example 1, the only difference is that the amount of the compound of formula IV and the amount of trifluoroacetic acid are controlled according to Table 3 to prepare compound III. The molar yields and purities of compound III are shown in table 3.
TABLE 3 molar yields and purities of the compound III obtained under different reaction conditions
| Step 3 | The amount of the compound of formula IV | The amount of trifluoroacetic acid | Molar yield | Purity of |
| Example 1 | 1.05eq. | 0.2eq. | 89％ | 97.3％ |
| Comparative experiment group 9 | 0.95eq. | 0.2eq. | 79％ | 92.3％ |
| Comparative experiment group 10 | 1.1eq. | 0.2eq. | 72％ | 85.6％ |
| Comparative experiment group 11 | 1.2eq. | 0.2eq. | 58％ | 86.7 |
As can be seen from Table 3, when the amount of the compound of formula IV was 1.05eq. And the amount of trifluoroacetic acid was 0.2eq. The molar yield and purity of the obtained compound III were highest.
In summary, 1.02eq. Equivalents of compound VIII,1.15eq. Equivalents of cesium carbonate, 3.0eq. Equivalents of compound VI,4.5eq. Equivalents of triethylamine, 1.05eq. Equivalents of compound IV,0.2eq. Equivalents of trifluoroacetic acid are selected for the preparation of 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one, which is the best process parameter.
The invention provides a method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone. Compared with the method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazine-3 (2H) -ketone in the prior art, the method for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazine-3 (2H) -ketone has the advantages of simpler synthetic route, higher reaction selectivity and easily obtained raw materials, and is suitable for industrial production.
Claims (10)
1. A process for preparing 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropylpyridazin-3 (2H) -one, characterized by: the method comprises the following steps:
(1) The compound V and the compound IV react under the action of a catalyst, acid and a free radical initiator to obtain a compound III;
(2) Reacting the compound III with alkali to obtain a compound II;
(3) The compound II reacts with alkali to obtain the compound I, namely 6- (4-amino-2, 6-dichlorophenoxy) -4-isopropyl pyridazin-3 (2H) -ketone.
2. The method according to claim 1, characterized in that: in the step (1), the feeding mode of the reaction is as follows: firstly, mixing a compound V, a compound IV, a catalyst and acid in a solvent for reaction, and then adding a solution of a free radical initiator; the mol ratio of the compound V to the compound IV to the catalyst to the acid to the free radical initiator is 1 (0.95-1.1): 0.1-0.2): 2-3; the acid is an organic acid, the free radical initiator is a polysulfide, and the catalyst is silver salt; the solvent of the reaction is an inorganic solvent; the reaction temperature is 65-85 ℃ and the reaction time is 0.5-3 hours;
And/or in the step (2), the molar ratio of the compound III to the alkali is 1 (3-4); the alkali is an organic alkali; the solvent of the reaction is an organic solvent; the temperature of the reaction is 90-110 ℃ and the time is 20-30 hours;
And/or, in the step (3), the molar ratio of the compound II to the alkali is 1 (9-11); the alkali is inorganic alkali; the solvent for the reaction is a mixture of an organic solvent and water; the reaction temperature is 110-130 ℃ and the reaction time is 10-14 hours.
3. The method according to claim 2, characterized in that: in the step (1), the molar ratio of the compound V to the compound IV to the catalyst to the acid to the free radical initiator is 1:1.05:0.1:0.2:2; the acid is trifluoroacetic acid, the persulfate is persulfate, preferably ammonium persulfate, and the catalyst is silver nitrate; the solvent of the reaction is water; the temperature of the reaction is 70 ℃ and the time is 1-2 hours;
and/or in step (2), the molar ratio of compound III to base is 1:3.5; the alkali is sodium acetate; the solvent of the reaction is acetic acid; the temperature of the reaction is 100 ℃ and the time is 24 hours;
In the step (3), the molar ratio of the compound II to the alkali is 1:10; the alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide; the organic solvent is methanol; the temperature of the reaction was 120℃for 12 hours.
4. The method according to claim 1, characterized in that: after the reaction of the step (1) is finished, the method further comprises the following purification steps: cooling the reaction solution to 0 ℃, adding alkali to adjust the pH to be=9, extracting by ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove ethyl acetate, pulping and purifying a crude product by using a mixed solution of n-heptane and ethyl acetate, and drying to obtain a compound III;
And/or, after the reaction in the step (2) is finished, the method further comprises the following purification steps: adding water into the reaction solution, and crystallizing; filtering, pulping and purifying a filter cake by using water, and drying the obtained crude product by using a mixed solution of n-heptane and ethyl acetate to obtain a compound II;
And/or, after the reaction in the step (3) is finished, the method further comprises the following purification steps: the reaction solution is concentrated under reduced pressure to remove the solvent, water is added to separate out the crude product, and the crude product is filtered, pulped and purified by methyl tertiary butyl ether and dried to obtain the compound I.
5. The method according to any one of claims 1-4, wherein: the preparation method of the compound V comprises the following steps:
And (3) reacting the compound VII with the compound VI under the action of alkali to obtain a compound V.
6. The method according to claim 5, wherein: the molar ratio of the compound VII, the compound VI and the alkali is 1: (2.5-3.5): (3.0-5.0), wherein the base is an organic base; the solvent of the reaction is an organic solvent; the reaction temperature is 0-35 ℃ and the reaction time is more than 6 hours.
7. The method according to claim 6, wherein: the molar ratio of the compound VII, the compound VI and the alkali is 1:3:4.5, wherein the base is triethylamine or N, N-diisopropylethylamine; the solvent of the reaction is dichloromethane; the reaction temperature is 0-25 ℃ and the reaction time is 8-10 hours.
8. The method according to claim 5, wherein: the preparation method of the compound VII comprises the following steps:
The compound IX and the compound VIII react under the action of alkali to obtain the compound VII.
9. The method according to claim 8, wherein: the molar ratio of the compound IX to the compound VIII to the base is 1: (0.9-1.1): (1.1-1.2), wherein the alkali is an inorganic alkali, and the solvent for the reaction is an organic solvent; the reaction temperature is 60-120 ℃ and the reaction time is more than 19 hours.
10. The method according to claim 9, wherein: the molar ratio of the compound IX to the compound VIII to the base is 1:1.02:1.15, wherein the base is potassium carbonate, cesium carbonate or sodium carbonate, and the solvent for the reaction is N, N-dimethylacetamide, N-dimethylformamide or dimethyl sulfoxide; the reaction temperature is 70-110 ℃ and the reaction time is more than 19 hours.
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