CN117924273A - Preparation method of non-neridrone bulk drug - Google Patents
Preparation method of non-neridrone bulk drug Download PDFInfo
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- CN117924273A CN117924273A CN202410018862.0A CN202410018862A CN117924273A CN 117924273 A CN117924273 A CN 117924273A CN 202410018862 A CN202410018862 A CN 202410018862A CN 117924273 A CN117924273 A CN 117924273A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 21
- YMXQYZABFWVXEK-UHFFFAOYSA-N 4-bromo-2-methoxybenzaldehyde Chemical compound COC1=CC(Br)=CC=C1C=O YMXQYZABFWVXEK-UHFFFAOYSA-N 0.000 claims abstract description 11
- GCPWJFKTWGFEHH-UHFFFAOYSA-N acetoacetamide Chemical compound CC(=O)CC(N)=O GCPWJFKTWGFEHH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940088679 drug related substance Drugs 0.000 claims abstract description 10
- 239000000276 potassium ferrocyanide Substances 0.000 claims abstract description 9
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 claims abstract description 9
- SSQZBQXJYGNUSC-UHFFFAOYSA-N 4-amino-5-methyl-1h-pyridin-2-one Chemical compound CC1=CNC(=O)C=C1N SSQZBQXJYGNUSC-UHFFFAOYSA-N 0.000 claims abstract description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 3
- 239000011975 tartaric acid Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- DXDIHODZARUBLA-DTPOWOMPSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid;hydrate Chemical compound O.O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 DXDIHODZARUBLA-DTPOWOMPSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000010669 acid-base reaction Methods 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- -1 potassium ferricyanide Chemical compound 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims 1
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 229940083712 aldosterone antagonist Drugs 0.000 description 4
- 208000020832 chronic kidney disease Diseases 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000003637 steroidlike Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- BTBHLEZXCOBLCY-QGZVFWFLSA-N (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide Chemical compound C1([C@@H]2C(=C(C)NC=3C(C)=CN=C(C2=3)OCC)C(N)=O)=CC=C(C#N)C=C1OC BTBHLEZXCOBLCY-QGZVFWFLSA-N 0.000 description 1
- GNENVASJJIUNER-UHFFFAOYSA-N 2,4,6-tricyclohexyloxy-1,3,5,2,4,6-trioxatriborinane Chemical compound C1CCCCC1OB1OB(OC2CCCCC2)OB(OC2CCCCC2)O1 GNENVASJJIUNER-UHFFFAOYSA-N 0.000 description 1
- SWJVFAOGXDGTCX-UHFFFAOYSA-N 2-cyanoethyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OCCC#N SWJVFAOGXDGTCX-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229950004408 finerenone Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a non-nefarious drug, belonging to the technical field of organic synthesis and preparation of drug substances. 4-bromo-2-methoxybenzaldehyde and acetyl acetamide are adopted as raw materials to obtain an intermediate 1 through condensation; intermediate 1 and 4-amino-5-methylpyridin-2-one are dehydrated and cyclized to obtain intermediate 2; intermediate 2 is O-alkylated to obtain intermediate 3; intermediate 3 is subjected to tartaric acid chiral resolution to obtain intermediate 4; intermediate 4 is coupled with potassium ferrocyanide to obtain the non-neridrone raw material. According to the invention, 4-bromo-2-methoxybenzaldehyde and acetyl acetamide are adopted as raw materials, so that the raw materials are economical and easy to obtain, the synthesis cost is reduced, and the economic benefit is improved; the method has mild reaction conditions, and improves the safety and production efficiency of the reaction; the invention has higher comprehensive yield and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of bulk drugs, and relates to a preparation method of a non-neridrone bulk drug.
Background
Non-nerlidone is the first non-steroidal selective mineralocorticoid receptor antagonist to confirm the benefit of kidney and cardiovascular disease in patients with chronic kidney disease combined with type 2 diabetes. On day 7 and 9 of 2021, bayer announced that the first non-steroidal selective mineralocorticoid receptor antagonist, non-nefarious ketone (Ke-rendia), was marketed in the united states by the Food and Drug Administration (FDA). Non-nefarnesone (10 mg or 20 mg) can be used to reduce the risk of sustained EGFR decline, end-stage renal disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease and type 2 diabetes. The European drug administration (EMA) human medical product Committee (CHMP) recommended approval of the non-steroidal selective mineralocorticoid receptor antagonist, non-neridone, for sale at month 12 2021. Once approved, non-nerlidone will be the first non-resident selective mineralocorticoid receptor antagonist for improving the prognosis of the kidney in adult patients with chronic kidney disease with type 2 diabetes.
The non-naphthalene Li Tonghua structure is shown below:
Currently, patent document US2018244668A1 discloses a process for the preparation of non-nelidane (Finerenone), using 2-cyanoethyl 3-oxobutyrate as starting material, the synthetic route of which is as follows:
the prior art mainly has the following problems:
1) The patent is protected and cannot be used for commercial production;
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a novel preparation method of a non-nefarious drug substance, which can effectively improve the reaction efficiency and the safety.
The technical scheme adopted by the invention is as follows: a preparation method of a non-nefarone bulk drug, which comprises the following steps:
step one: condensing 4-bromo-2-methoxybenzaldehyde and acetyl acetamide serving as raw materials to obtain an intermediate 1 with a structural formula shown as (I):
step two: the intermediate 1 and 4-amino-5-methylpyridin-2-one are dehydrated and cyclized to obtain an intermediate 2 with a structural formula shown as (II):
step three: o-alkylation of intermediate 2 gives intermediate 3 of formula (III):
Step four: intermediate 3 is resolved by tartaric acid to obtain intermediate 4 with a structural formula shown In (IV):
Step five: the intermediate 4 is coupled with potassium ferrocyanide to obtain a non-neridrone raw material with a structural formula shown as (V):
The synthetic route is as follows:
In the present invention, the preparation method of the non-nefarnesone intermediate 1 preferably adopts the following reaction conditions:
the raw materials used are 4-bromo-2-methoxybenzaldehyde and acetyl acetamide;
the solvent is isopropanol or dichloromethane;
The acid used is an organic acid;
the catalyst used is piperidine;
The molar ratio of the used raw materials is 4-bromo-2-methoxybenzaldehyde: acetyl acetamide: piperidine: acetic acid=1: 1.5:0.1:0.1;
The reaction temperature is 30-50 ℃;
the reaction time is 8-10 hours.
In the present invention, a preferred method for preparing the non-nelidamide intermediate 2 is:
The molar ratio of the intermediate 1 to the 4-amino-5-methylpyridin-2-one is 1:1-1.2;
the solvent is dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide or alcohol solvent;
the reaction temperature is 90-140 ℃;
The reaction time is 10-20 hours;
And (3) after the reaction, obtaining an intermediate 2 through post-treatment, wherein the post-treatment is to cool to the temperature of T=0-5 ℃ after the reaction is finished, stir for 3-5 hours, suction-filter, and wash a filter cake with a small amount of dilute hydrochloric acid and ethyl acetate to obtain the non-nefaridone intermediate 2.
In the present invention, a preferred method for preparing the non-nelidamide intermediate 3 is:
The molar ratio of the raw materials is intermediate 2: triethyl orthoformate: sulfuric acid = 1:1.5:1, a step of;
the solvent is N, N-dimethylformamide or N, N-dimethylacetamide;
The acid is concentrated sulfuric acid;
The reaction temperature is 110-130 ℃;
the reaction time is 3-6 hours;
And (3) after the reaction, carrying out post-treatment to obtain a non-nefardone intermediate 3, wherein in the post-treatment, firstly, cooling to room temperature, slowly and dropwise adding water to separate out materials, then adding a proper amount of methanol, and stirring for 0.5 hour to separate out the non-nefardone intermediate 3.
In the present invention, a preferred method for preparing the non-nelidamide intermediate 4 is:
the solvent is one or more of dichloromethane, methanol, methyl isobutyl ketone, ethyl acetate and acetone;
The molar ratio of the raw materials is intermediate 3: (+) -dibenzoyl-L-tartaric acid monohydrate = 1:1, a step of;
the resolution temperature is 40-110 ℃;
the resolution time is 18-24 hours;
The alkali used is sodium hydroxide;
the pH value is 7.0-8.0;
The acid-base reaction temperature is 20-30 ℃;
The acid-base reaction time is 5-15 hours.
In the present invention, a preferred method for preparing the non-nelidamide intermediate 5 is:
the molar ratio of the raw materials is intermediate 4: potassium ferrocyanide: potassium carbonate: bis (triphenylphosphine) palladium (ii) dichloride=1: 0.25:2:0.05;
the solvent used was toluene: water = 3:1, 4-dioxane, N, N-dimethylformamide and dimethyl sulfoxide;
The coupling reagent used is potassium ferrocyanide;
The catalyst used is bis (triphenylphosphine) palladium (II) dichloride, palladium acetate, 1-bis (diphenylphosphino) ferrocene palladium dichloride;
the alkali is potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide;
The reaction temperature is 70-110 ℃;
The reaction time is 10-20 hours.
The preparation method of the non-nefarious drug substance is characterized by further comprising the following steps:
Step one, synthesis of intermediate 1:
adding 4-bromo-2-methoxybenzaldehyde into a reactor, sequentially adding acetyl acetamide, acetic acid, piperidine and isopropanol, and reacting at 30 ℃ for 24 hours; the solution is white in color, TLC detects that the raw materials are all reacted, and the reaction is stopped; cooling to T=0 ℃, stirring for 0.5 hour, separating out the material fully, filtering to obtain a filter cake, drying by pressing, and washing with saturated sodium bisulphite solution for 2 times to obtain an intermediate 1;
step two, synthesizing an intermediate 2:
Adding the intermediate 1 and dimethyl sulfoxide into a reactor, adding 4-amino-5-methylpyridin-2-one, heating to 140 ℃ and carrying out reflux reaction for 15 hours; a large amount of yellow solid appears, TLC detects that the reaction is complete, and the reaction is stopped; cooling to T=0-5 ℃, stirring for 4 hours, carrying out suction filtration, flushing a filter cake with a small amount of dilute hydrochloric acid and ethyl acetate, and obtaining a compound 2;
Step three, synthesizing an intermediate 3:
Adding an intermediate 2, triethyl orthoformate and N, N-dimethylacetamide into a reaction bottle; slowly dropwise adding sulfuric acid after heating to T=120 ℃ and reacting for 4 hours; after the reaction is finished, cooling to room temperature, slowly dripping water to separate out materials, adding 0.5ml of methanol, stirring for 0.5 hour, separating out yellow solid products, and drying to obtain an intermediate 3;
step four, synthesizing an intermediate 4:
The reaction flask was charged with intermediate 3, (+) -dibenzoyl-L-tartaric acid monohydrate and dichloromethane: methanol=15: 1, heating the reaction solution to 30-40 ℃ and stirring for 2-4 hours, then cooling to 20-25 ℃, stirring for 16 hours, filtering and drying to obtain split salt; then adding the split salt into a bottle, adding 250ml of water, dropwise adding saturated sodium bicarbonate aqueous solution to adjust the pH to 7-8, stirring overnight, filtering and drying to obtain a solid intermediate 4;
step five, synthesizing a non-neridrone raw material:
The intermediate 4, potassium ferrocyanide and potassium carbonate are added into a reaction bottle, and bis (triphenylphosphine) palladium (II) dichloride and toluene are added under the protection of nitrogen: water = 3:1, heating to 110 ℃ to react for 20 hours; after the reaction, cooling to room temperature, extracting and washing off toluene solvent and petroleum ether: ethyl acetate=20:1 column chromatography gave pure product.
Compared with the prior art, the method has the following beneficial effects:
according to the invention, 4-bromo-2-methoxybenzaldehyde and acetyl acetamide are adopted as raw materials, so that the raw materials are economical and easy to obtain, the synthesis cost is reduced, and the economic benefit is improved; the method has mild reaction conditions, and improves the safety and production efficiency of the reaction; the invention has higher comprehensive yield and is suitable for industrial production.
Detailed Description
The following further describes the technical solution of the present invention so that those skilled in the art may further understand the present invention without restricting the claims of the present invention.
Example 1, preparation method of non-nelidane bulk drug:
1. Synthesis of intermediate 1:
1) The synthetic route is as follows:
The specific method comprises the following steps: 2.15g (10 mmol) of 4-bromo-2-methoxybenzaldehyde were charged in the reactor, and 1.21g (12 mmol) of acetoacetamide, 0.06g (1 mmol) of acetic acid, 0.085g (1 mmol) of piperidine and 5ml of isopropyl alcohol were sequentially added and reacted at 30℃for 24 hours. The solution was white in color, and TLC detected almost all the starting materials reacted, stopping the reaction. Cooling to T=0deg.C, stirring for 0.5 hr, separating out the material, filtering to obtain filter cake, drying, washing with saturated sodium bisulphite solution twice to obtain intermediate 1, and obtaining yield 80％.1H NMR(500MHz,Chloroform-d)δ7.86(s,1H),7.67–7.60(m,2H),7.53(d,J＝7.1Hz,1H),7.35(dd,J＝9.0,2.2Hz,1H),7.11(d,J＝2.2Hz,1H),3.89(s,2H),2.29(s,3H).
2) The synthetic route is as follows:
The specific method comprises the following steps: 2.15g (10 mmol) of 4-bromo-2-methoxybenzaldehyde were charged in the reactor, and 1.21g (12 mmol) of acetoacetamide, 0.06g (1 mmol) of acetic acid, 0.085g (1 mmol) of piperidine and 5ml of methylene chloride were sequentially added to react at 30℃for 24 hours. TLC detects almost all starting materials reacted and stopped. Cooling to T=0deg.C, extracting with saturated sodium bisulphite solution, spin drying, and purifying by column chromatography to obtain intermediate 1 with yield 76％.1H NMR(500MHz,Chloroform-d)δ7.86(s,1H),7.67–7.60(m,2H),7.53(d,J＝7.1Hz,1H),7.35(dd,J＝9.0,2.2Hz,1H),7.11(d,J＝2.2Hz,1H),3.89(s,2H),2.29(s,3H).
2. Synthesis of intermediate 2:
1) The synthetic route is as follows:
The specific method comprises the following steps: into the reactor were added 2.98g (10 mmol) of intermediate 1 and 20ml of dimethyl sulfoxide, and 1.24g (10 mmol) of 4-amino-5-methylpyridin-2-one, and the mixture was heated to 140℃and reacted under reflux for 15 hours. A large amount of yellow solid appeared, TLC detected complete reaction, and stopped the reaction. Cooling to T=0-5 deg.c, stirring for 4 hr, suction filtering, flushing filter cake with dilute hydrochloric acid and ethyl acetate to obtain compound 2 in high yield 55％.1H NMR(500MHz,Chloroform-d)δ9.13(s,1H),7.41(dd,J＝7.1,1.5Hz,1H),7.28(dd,J＝8.6,2.0Hz,1H),7.22(dd,J＝8.6,0.7Hz,1H),7.18(d,J＝1.9Hz,1H),6.94(s,2H),4.95–4.71(m,1H),3.83(s,3H),2.15(d,J＝1.5Hz,3H),2.08(d,J＝1.1Hz,3H).
2) The synthetic route is as follows:
The specific method comprises the following steps: into the reactor were charged 2.98g (10 mmol) of intermediate 1 and 20ml of N, N-dimethylformamide, and 1.24g (10 mmol) of 4-amino-5-methylpyridin-2-one were further added, and the reaction was carried out at reflux at a temperature of 140℃for 15 hours. A large amount of yellow solid appeared, TLC detected complete reaction, and stopped the reaction. Cooling to T=0-5 deg.c, stirring for 4 hr, suction filtering, flushing filter cake with dilute hydrochloric acid and ethyl acetate to obtain compound 2 in high yield 49％.1H NMR(500MHz,Chloroform-d)δ9.13(s,1H),7.41(dd,J＝7.1,1.5Hz,1H),7.28(dd,J＝8.6,2.0Hz,1H),7.22(dd,J＝8.6,0.7Hz,1H),7.18(d,J＝1.9Hz,1H),6.94(s,2H),4.95–4.71(m,1H),3.83(s,3H),2.15(d,J＝1.5Hz,3H),2.08(d,J＝1.1Hz,3H).
Synthesis of intermediate 3:
The synthetic route is as follows:
The specific method comprises the following steps: into the reaction flask were charged 4.03g (10 mmol) of intermediate 2, 2.2g (15 mmol) of triethyl orthoformate and 10ml of N, N-dimethylacetamide. After heating to t=120℃, 0.54ml (10 mmol) of sulfuric acid was slowly added dropwise thereto and the reaction was carried out for 4 hours. After the reaction is finished, the temperature is reduced to room temperature, water is slowly added dropwise for precipitation, 0.5ml of methanol is added for stirring for 0.5 hour, a yellow solid product is precipitated, and the obtained intermediate 3 is dried, so that the yield is improved 90％.1HNMR(500MHz,Chloroform-d)δ9.93(s,1H),7.95(d,J＝0.8Hz,1H),7.32(d,J＝1.6Hz,2H),7.15(dd,J＝1.6,0.8Hz,1H),7.04(s,2H),5.11(q,J＝1.1Hz,1H),4.31(q,J＝6.7Hz,2H),3.83(s,3H),2.21(d,J＝0.7Hz,3H),2.12(d,J＝1.1Hz,3H),1.46(d,J＝13.3Hz,3H).
3. Synthesis of intermediate 4:
1) The synthetic route is as follows:
The specific method comprises the following steps: 4.31g (10 mmol) of the intermediate 3,3.6g of (+) -dibenzoyl-L-tartaric acid monohydrate and 32ml of mixed solvent (dichloromethane: methanol=15:1) are added into a reaction bottle, the reaction solution is heated to 30-40 ℃ and stirred for 2-4 hours, then cooled to 20-25 ℃, stirred for 16 hours, filtered and dried to obtain split salt. The split salt was then added to a bottle, 250ml of water was added, saturated aqueous sodium bicarbonate was added dropwise to adjust ph=7-8, stirred overnight, filtered and dried to give a solid (intermediate 4). The yield was 90.2% and the ee value was 99.4%.
2) The synthetic route is as follows:
the specific method comprises the following steps: 4.31g (10 mmol) of intermediate 3,3.6g of (+) -dibenzoyl-L-tartaric acid monohydrate and 32ml of ethyl acetate as a mixed solvent are added into a reaction bottle, the reaction solution is heated to 70-80 ℃ and stirred for 2-4 hours, then cooled to 20-25 ℃, stirred for 16 hours, filtered and dried to obtain split salt. The split salt was then added to a bottle, 250ml of water was added, saturated aqueous sodium bicarbonate was added dropwise to adjust ph=7-8, stirred overnight, filtered and dried to give a solid (intermediate 4). The yield thereof was found to be 91.6% and the ee value thereof was found to be 99.0%.
3) The synthetic route is as follows:
The specific method comprises the following steps: 4.31g (10 mmol) of intermediate 3,3.6g of (+) -dibenzoyl-L-tartaric acid monohydrate and 32ml of methyl isobutyl ketone as a mixed solvent are added into a reaction bottle, the reaction solution is heated to 60-70 ℃ and stirred for 2-4 hours, then cooled to 20-25 ℃, stirred for 16 hours, filtered and dried to obtain split salt. The split salt was then added to a bottle, 250ml of water was added, saturated aqueous sodium bicarbonate was added dropwise to adjust ph=7-8, stirred overnight, filtered and dried to give a solid (intermediate 4). The yield was 90.0% and the ee value was 98.3%.
4. Synthesis of non-neridone bulk drug:
1) The synthetic route is as follows:
The specific method comprises the following steps: to a reaction flask were added 4.31g (10 mmol) of intermediate 4, 0.92g (0.25 mmol) of potassium ferrocyanide, 2.76g (20 mmol) of potassium carbonate, and under nitrogen protection, 0.362g of bis (triphenylphosphine) palladium (II) dichloride and toluene: water = 3:1, and the temperature is raised to 110 ℃ for reaction for 20 hours. After the reaction, cooling to room temperature, extracting and washing off toluene solvent, and performing column chromatography (petroleum ether: ethyl acetate=20:1) to obtain a pure product with yield 94.1％.1H NMR(500MHz,DMSO-d6)δ7.69(s,1H),7.55(s,1H),7.37(d,J＝1.6Hz,1H),7.28(dd,J＝7.9,1.5Hz,1H),7.15(d,J＝7.8Hz,1H),6.90–6.55(m,2H),5.38(s,1H),4.01(dq,J＝7.2,3.2Hz,2H),3.82(s,3H),2.19(s,3H),2.12(s,3H),1.05(t,J＝7.0Hz,3H).
2) The synthetic route is as follows:
The specific method comprises the following steps: to a reaction flask were added 4.31g (10 mmol) of intermediate 4, 0.82g (0.25 mmol) of potassium ferricyanide, 2.76g (20 mmol) of potassium carbonate, and under nitrogen protection, 0.362g of bis (triphenylphosphine) palladium (ii) dichloride and toluene: water = 3:1, and the temperature is raised to 110 ℃ for reaction for 20 hours. After the reaction, cooling to room temperature, extracting and washing off toluene solvent, and performing column chromatography (petroleum ether: ethyl acetate=20:1) to obtain a pure product with yield 93.4％.1H NMR(500MHz,DMSO-d6)δ7.69(s,1H),7.55(s,1H),7.37(d,J＝1.6Hz,1H),7.28(dd,J＝7.9,1.5Hz,1H),7.15(d,J＝7.8Hz,1H),6.90–6.55(m,2H),5.38(s,1H),4.01(dq,J＝7.2,3.2Hz,2H),3.82(s,3H),2.19(s,3H),2.12(s,3H),1.05(t,J＝7.0Hz,3H).
Claims (8)
1. A preparation method of a non-nelidone bulk drug is characterized by comprising the following steps: comprising the following steps:
step one: condensing 4-bromo-2-methoxybenzaldehyde and acetyl acetamide serving as raw materials to obtain an intermediate 1 with a structural formula shown as (I):
step two: the intermediate 1 and 4-amino-5-methylpyridin-2-one are dehydrated and cyclized to obtain an intermediate 2 with a structural formula shown as (II):
step three: o-alkylation of intermediate 2 gives intermediate 3 of formula (III):
Step four: intermediate 3 is resolved by tartaric acid to obtain intermediate 4 with a structural formula shown In (IV):
Step five: the intermediate 4 is coupled with potassium ferrocyanide to obtain a non-neridrone raw material with a structural formula shown as (V):
2. The method for preparing a drug substance of non-nelidone according to claim 1, wherein in the first step: the solvent used for preparing the non-nefardone intermediate 1 is isopropanol or dichloromethane; the acid used is an organic acid; the catalyst used is piperidine; the reaction temperature is 30-50 ℃; the reaction time is 8-10 hours.
3. The method for preparing a drug substance of non-nelidone according to claim 1 or 2, wherein in step one: in the preparation of the non-neridone intermediate 1, the molar ratio of the raw materials is as follows: 4-bromo-2-methoxybenzaldehyde: acetyl acetamide: piperidine: acetic acid=1: 1.5:0.1:0.1.
4. The method for preparing a drug substance of non-nefarnesone according to claim 1, wherein in the second step, when preparing the non-nefarnesone intermediate 2, the molar ratio of the intermediate 1 to the 4-amino-5-methylpyridin-2-one is: 1:1-1.2; the solvent used is dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide or alcohol solvents; the reaction temperature is 90-140 ℃; the reaction time is 10-20 hours.
5. The method for preparing a non-nelidane bulk drug according to claim 1 or 4, which is characterized in that: in the second step, when the non-nefardone intermediate 2 is prepared, the intermediate 2 is obtained after the reaction, wherein the post-treatment is to cool to the temperature of between T=0 and 5 ℃ after the reaction is finished, stir for 3 to 5 hours, suction filter, and wash a filter cake with a small amount of dilute hydrochloric acid and ethyl acetate to obtain the non-nefardone intermediate 2.
6. The method for preparing a non-nefarious drug substance according to claim 1, wherein in the third step, when preparing the non-nefarious drug substance 3, the molar ratio of the raw materials is: intermediate 2: triethyl orthoformate: sulfuric acid = 1:1.5:1, a step of; the solvent is N, N-dimethylformamide or N, N-dimethylacetamide; the acid is concentrated sulfuric acid; the reaction temperature is 110-130 ℃; the reaction time is 3-6 hours; the intermediate 3 is obtained after the reaction and the post-treatment method is that firstly, the temperature is reduced to the room temperature, water is dripped into the mixture for precipitation, then a proper amount of methanol is added into the mixture for stirring, and the non-nereirenone intermediate 3 is precipitated.
7. The method for preparing a non-nefarnesone drug substance according to claim 1, wherein in the fourth step, the solvent used in the preparation of the non-nefarnesone intermediate 4 is one or more of dichloromethane, methanol, methyl isobutyl ketone, ethyl acetate and acetone; the molar ratio of the raw materials is as follows, intermediate 3: (+) -dibenzoyl-L-tartaric acid monohydrate fraction=1: 1, a step of; the dismantling temperature is 40-110 ℃; the resolution time is 18-24 hours; the alkali used is sodium hydroxide; adjusting pH to 7.0-8.0; the acid-base reaction temperature is 20-30 ℃; the acid-base reaction time is 5-15 hours.
8. The method for preparing a drug substance of non-nefarious ketone according to claim 1, wherein in the fifth step, when preparing the non-nefarious ketone intermediate 5, the molar ratio of the raw materials is: intermediate 4: potassium ferrocyanide: potassium carbonate: bis (triphenylphosphine) palladium (ii) dichloride=1: 0.25:2:0.05; the reaction solvent is selected from toluene: water = 3:1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide or acetonitrile;
the coupling reagent for reaction is potassium ferrocyanide or potassium ferricyanide;
The catalyst for the reaction is selected from bis (triphenylphosphine) palladium (II) dichloride, palladium acetate or 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride;
the reaction base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide;
The reaction temperature is 70-130 ℃;
The reaction time is 10-20 hours.
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