CN104649882A - Intermediate preparation process of phosphodiesterase inhibitor - Google Patents
Intermediate preparation process of phosphodiesterase inhibitor Download PDFInfo
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- CN104649882A CN104649882A CN201510071703.8A CN201510071703A CN104649882A CN 104649882 A CN104649882 A CN 104649882A CN 201510071703 A CN201510071703 A CN 201510071703A CN 104649882 A CN104649882 A CN 104649882A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 title claims abstract description 15
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title claims abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 70
- 239000007806 chemical reaction intermediate Substances 0.000 claims abstract description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000000543 intermediate Substances 0.000 claims abstract description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 5
- 238000010992 reflux Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 23
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 16
- 238000004821 distillation Methods 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 11
- -1 fluorobenzoyl cyclohexene Chemical compound 0.000 claims description 11
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- RAAGZOYMEQDCTD-UHFFFAOYSA-N 2-fluorobenzoyl chloride Chemical compound FC1=CC=CC=C1C(Cl)=O RAAGZOYMEQDCTD-UHFFFAOYSA-N 0.000 claims description 5
- IIQFBBQJYPGOHJ-UHFFFAOYSA-N 4-(cyclohexen-1-yl)morpholine Chemical compound C1CCCC(N2CCOCC2)=C1 IIQFBBQJYPGOHJ-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 239000006227 byproduct Substances 0.000 claims description 4
- 238000004064 recycling Methods 0.000 claims description 4
- 230000000630 rising effect Effects 0.000 claims description 4
- KPVMGWQGPJULFL-UHFFFAOYSA-N 1-(cyclohexen-1-yl)piperidine Chemical group C1CCCCN1C1=CCCCC1 KPVMGWQGPJULFL-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 2
- WDKMRHPBPTUYDX-UHFFFAOYSA-N (4-oxocyclohexyl) 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1CCC(=O)CC1 WDKMRHPBPTUYDX-UHFFFAOYSA-N 0.000 abstract 1
- YPFGOHKUMTXOKV-UHFFFAOYSA-N 2-(4-fluorobenzoyl)cyclohexan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)C1C(=O)CCCC1 YPFGOHKUMTXOKV-UHFFFAOYSA-N 0.000 abstract 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 abstract 1
- 229940055858 aluminum chloride anhydrous Drugs 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/562—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation process of an intermediate of a phosphodiesterase inhibitor. The preparation process comprises the following steps: carrying out a synthetic reaction on a heterocyclic compound, cyclohexanone, p-toluenesulfonate monohydrate and methylbenzene, distilling to remove the methylbenzene and incompletely reacted heterocyclic compound, and dissolving a first reaction intermediate by virtue of dichloromethane so as to obtain a first product; carrying out a synthetic reaction on aluminum chloride anhydrous, dichloromethane, p-fluorobenzoyl chloride and the first product, thinning with water so as to separate the materials into a water layer and an oil layer, and extracting the water layer with dichloromethane so as to obtain a second product; and mixing the second product with dioxane and hydrochloric acid and carrying out a heating reflux reaction, removing a solvent through distilling, dissolving with dichloromethane, washing with a saturated sodium carbonate solution, drying with anhydrous sodium sulfate and distilling to remove dichloromethane so as to obtain an intermediate, namely 2-(4-fluorobenzoyl) cyclohexanone, functioning as a phosphodiesterase inhibitor, wherein the yield is 65-68%, and raw materials adopted by the preparation process are easily available and economic benefit can be improved.
Description
Technical field
The invention relates to a kind of preparation technology of intermediate of phosphodiesterase inhibitor, is more particularly the preparation technology of the intermediate of a kind of Friedel-Crafts reaction synthesis phosphodiesterase inhibitor.
Background technology
Phosphodiesterase inhibitor (phosphodiesteras, PDEs) is a kind of medicine suppressing phosphodiesterase activity.The diversity of phosphodiesterase inhibitor superfamily and complicacy are that the treatment of various diseases provides new clue.Such as, selective PDE enzyme 3,4,5 inhibitor are with a wide range of applications in the diseases such as heart failure, asthma, impotence.Preparation technology's difficulty of the intermediate of phosphodiesterase inhibitor is higher.The intermediate of phosphodiesterase inhibitor has document and adopts lithium diisopropylamine (LDA) or two (trimethyl silicon based) Lithamide (LHMDS) method to prepare, with pimelinketone and to fluorobenzoyl chloride for raw material, but these two kinds of methods must in-78 degree and-20 degree reactions, and will in anhydrous and oxygen-free condition, reaction conditions is very harsh.Or adopt organic Au catalyst, with cyclonene and parafluorobenzoic acid for raw material, but organic Au catalyst is expensive and be difficult to obtain.Be exactly adopt organic golden catalysis in addition, with cyclonene and parafluorobenzoic acid for raw material, this method expensive catalyst, should not buy.At open source literature " Fragment based lead discovery of smallmolecule " (European Journal of Medicinal Chemistry v47, p493-500, 2012) and " Pyrimido [4, 5-c/] isoquinolines.2.Synthesis and Biological Evaluation of Some6-Alkyl-6-Aralkyl-, and 6-Aryl-1, 3-diamino-7, 8, 9, 10-tetrahydropyrimido [4, 5-c] isoquinolones as Potential FolateAntagonists " (Journal of Medicinal Chemistry, V17, No 12, 1974) preparation technology of report intermediate is had in, the yield of the operational path reality disclosed by above-mentioned document is very low, subject matter is the more difficult purification of reaction product, also just represent that this method disclosed by two sections of documents above-mentioned lacks the actual application value of suitability for industrialized production.
Summary of the invention
For solving the problem and blemish existing for prior art, main purpose of the present invention is to provide a kind of synthesis route preparing the intermediate of phosphodiesterase inhibitor, with heterogeneous ring compound, pimelinketone and tosic acid one water thing are as raw material, based on the demand, main purpose of the present invention provides a kind of with heterogeneous ring compound, pimelinketone and tosic acid one water thing are as the raw material of intermediate preparing phosphodiesterase inhibitor, simple and the raw material of its processing sequence is easy to obtain, and the yield of the intermediate 2-obtained (4-fluoro benzoyl) pimelinketone comparatively document is high, the tangible industry applications of its tool, the cost of the intermediate preparing phosphodiesterase inhibitor can be reduced.
For reaching above-mentioned purpose, the present invention adopts a kind of preparation technology of intermediate of phosphodiesterase inhibitor, it is characterized in that, step comprises (1) by heterogeneous ring compound, pimelinketone, tosic acid one water thing and toluene carry out mixing and pass into rare gas element and carries out building-up reactions to obtain the first reaction intermediates and the first by product, distilled is to remove toluene and unreacted heterogeneous ring compound completely, recycling methylene dichloride dissolves the first reaction intermediates, and with saturated sodium bicarbonate solution washing, drying is carried out with anhydrous sodium sulphate, distillation is utilized to remove methylene dichloride to obtain the first product, (2) by aluminum trichloride (anhydrous), methylene dichloride, carry out building-up reactions to fluorobenzoyl chloride and the first product, to obtain the second reaction intermediates, thin up second reaction intermediates, the second reaction intermediates is made to be divided into water layer and oil reservoir, methylene dichloride is utilized to extract to water layer, to obtain the second product, and the second product, dioxane and mixed in hydrochloric acid are carried out temperature rising reflux reaction by (3), recycling distillation removes solvent to obtain the 3rd reaction intermediates, then methylene dichloride is utilized to dissolve the 3rd reaction intermediates, again with saturated sodium carbonate solution 50ml washing, and with anhydrous sodium sulfate drying, distillation removes methylene dichloride to obtain third product, 2-(4-fluoro benzoyl) pimelinketone.
Embodiment
Embodiment 1: preparation 1-(1-cyclohexenyl) piperidines
Heterogeneous ring compound is added in the reaction flask of 1L, such as piperidines (also known as hexahydropyridine) (Piperdine), 156g, pimelinketone 121g, tosic acid one water thing 2.6g and toluene 450ml mix, and load onto water trap on reaction flasks, pass into rare gas element such as, argon gas, replace three times, be warming up to backflow, can separate by product in this step is that water is about 20g, until react completely to obtain the first reaction intermediates, this first reaction intermediates is liquid.Then, the first reaction intermediates is removed toluene and unreacted heterogeneous ring compound completely in the mode of air distillation, piperidines.Next, by methylene dichloride (DCM, dichloromethane) 1000ml adds the first reaction intermediates and dissolves, the saturated sodium bicarbonate aqueous solution 200ml of mother liquor after dissolving washs to remove the tosic acid contained by the first reaction intermediates, and carry out drying with anhydrous sodium sulphate, utilize distillation to remove methylene dichloride to obtain the first product, 1-(1-cyclohexenyl) piperidines, its yield is about 85%.
Embodiment 2: prepare piperidino-2-to fluorobenzoyl cyclohexene
Aluminum trichloride (anhydrous) 24.1g is added and methylene dichloride 400ml mixes and stirs 30-40 minute in the reaction flask of 500ml, and then add to fluorobenzoyl chloride 22g in the above-mentioned reaction solution mixed, and the temperature of reaction solution is cooled to 0 degree to form the second reaction intermediates.Then, the first product slowly will prepared by embodiment 1,1-(1-cyclohexenyl) piperidinyl-1 9.5g, drops to the second reaction intermediates, and in stirred at ambient temperature 2 hours until react completely after being added dropwise to complete, this second reaction intermediates is liquid.Afterwards, utilize the water of 500ml to dilute the second reaction intermediates, and stir 30 minutes, make the second reaction intermediates be divided into oil reservoir and water layer.For the water layer of the second reaction intermediates; methylene dichloride 200ml is utilized to carry out extracting to be extracted liquid; recycle saturated saleratus solution 200ml to wash; and with anhydrous sodium sulfate drying; the second product is obtained after evaporate to dryness; pale yellow oil piperidino-2-to fluorobenzoyl cyclohexene, its yield about 63%.
Embodiment 3: preparation 2-(4-fluoro benzoyl) pimelinketone
In the reaction flask of 100ml, add the second product prepared by embodiment 2, piperidino-2-is the hydrochloric acid 10ml of 10% to fluorobenzoyl cyclohexene 10g, dioxane 50ml and concentration, reacts 5 hours in the mode of temperature rising reflux.After reaction terminates; the 3rd reaction intermediates is obtained after utilizing distillation removal solvent; this the 3rd reaction intermediates is solid, and dissolves with 200ml methylene dichloride, then washs with saturated sodium carbonate solution 50ml; and with anhydrous sodium sulfate drying; methylene dichloride is removed in distillation, to obtain the 3rd reactant, and 2-(4-fluoro benzoyl) pimelinketone; it is yellow solid, and yield is 65%.
The present invention also discloses the preparation technology of another 2-(4-fluoro benzoyl) pimelinketone, as described in following examples 4-6.
Embodiment 4: preparation 1-(1-cyclohexenyl) morpholine
Heterogeneous ring compound is added in the reaction flask of 1L, such as morpholine, 160g, pimelinketone 121g, tosic acid one water thing 2.6g and toluene 450ml, and water trap is loaded onto on reaction flask, pass into rare gas element argon gas and replace three times, be warming up to backflow, can separate by product in this step is water, about 20g, until react completely to obtain the 4th reaction intermediates.Then, by the 4th reaction intermediates in the mode of air distillation, remove toluene and unreacted heterogeneous ring compound, morpholine, in reaction flask, add methylene dichloride 1000ml again dissolve, the mother liquor after dissolving carries out washing to remove the tosic acid contained by the 4th reaction intermediates with saturated sodium bicarbonate aqueous solution 200ml, then uses anhydrous sodium sulfate drying, and distillation removes methylene dichloride to obtain the 4th product, 1-(1-cyclohexenyl) morpholine.
Embodiment 5: preparation 1-morpholinyl-2-is to fluorobenzoyl cyclohexene
In 500ml reaction flask, adding aluminum trichloride (anhydrous) 24.1g and methylene dichloride 400ml, through stirring 30 minutes, and then adding fluorobenzoyl chloride 22g, and reaction solution is cooled to 0 degree to form the 5th reaction intermediates.Then the 4th product slowly will prepared by embodiment 4,1-(1-cyclohexenyl) morpholine, 20.5g drops in reaction flask, and reacts with the 5th reaction intermediates, after being added dropwise to complete, under room temperature, carry out stirring 2 hours until react completely.Then, utilize the water of 500ml by the 5th reaction intermediates dilution and stir 30 minutes, making the 5th reaction intermediates be divided into oil reservoir and water layer.For the water layer of the 5th reaction intermediates; methylene dichloride is utilized to carry out extracting to be extracted liquid; and wash with the saturated saleratus solution of 200ml; use the slow drying of anhydrous slufuric acid again; the 5th product is obtained after evaporate to dryness; 1-morpholinyl-2-is to fluorobenzoyl cyclohexene, and it is pale yellow oil, and yield is about 66%.
Embodiment 6: preparation 2-(4-fluoro benzoyl) pimelinketone
In the reaction flask of 100ml, add the 5th product prepared by previous embodiment 5,1-morpholinyl-2-to fluorobenzoyl cyclohexene, 10g, dioxane 50ml and concentration be 10% hydrochloric acid 10ml mix, and temperature rising reflux reacts 5 hours.After reaction terminates; to obtain the 6th reaction intermediates after utilizing distillation removal solvent; this the 6th reaction intermediates is solid and dissolves with 200ml methylene dichloride; wash with saturated sodium carbonate solution again; and with anhydrous sodium sulfate drying; distillation is to remove the methylene dichloride contained by the 6th reaction intermediates; again with water content lower than 10% dehydrated alcohol make its crystallization again; filter and obtain the 6th product after drying; 2-(4-fluoro benzoyl) pimelinketone; it is white crystal, and yield is 68%.
Therefore the intermediate that obtains of preparation technology according to the present invention, 2-(4-fluoro benzoyl) pimelinketone, has higher yield and has the actual application value of suitability for industrialized production.
The above embodiment, just preferred embodiment of the present invention, not be used for limiting the scope of the present invention, therefore all equivalences done according to structure, feature and the principle described in the present patent application the scope of the claims change or modify, and all should be included in patent claim of the present invention.The reagent used in the various embodiments described above, as not dated especially, is all buied by open channel.
Claims (7)
1. a preparation technology for the intermediate of phosphodiesterase inhibitor, is characterized in that, described preparation technology comprises the following steps:
(1) heterogeneous ring compound, pimelinketone, tosic acid one water thing and toluene are carried out mixing and passes into rare gas element carry out building-up reactions, to obtain the first reaction intermediates and the first by product, distillation is to remove described toluene and unreacted described heterogeneous ring compound completely, recycling methylene dichloride dissolves described first reaction intermediates, and with saturated sodium bicarbonate solution washing, carry out drying with anhydrous sodium sulphate, utilize distillation to remove described methylene dichloride to obtain the first product;
(2) by aluminum trichloride (anhydrous), methylene dichloride, carry out building-up reactions to fluorobenzoyl chloride and described first product, to obtain the second reaction intermediates, second reaction intermediates described in thin up, make described second reaction intermediates be divided into water layer and oil reservoir, utilize methylene dichloride to extract to obtain the second product to described water layer; And
(3) described second product, dioxane and mixed in hydrochloric acid are carried out temperature rising reflux reaction, recycling distillation removes solvent to obtain the 3rd reaction intermediates, then methylene dichloride is utilized to dissolve described 3rd reaction intermediates, wash with saturated sodium carbonate solution again, and with anhydrous sodium sulfate drying, distill and remove described methylene dichloride to obtain third product.
2. preparation technology as claimed in claim 1, it is characterized in that, described heterogeneous ring compound is piperidines or morpholine.
3. preparation technology as claimed in claim 1, it is characterized in that, described rare gas element is argon gas.
4. preparation technology as claimed in claim 1, it is characterized in that, described first product is 1-(1-cyclohexenyl) piperidines or 1-(1-cyclohexenyl) morpholine.
5. preparation technology as claimed in claim 1, is characterized in that, described second product is piperidino-2-to fluorobenzoyl cyclohexene or 1-morpholinyl-2-to fluorobenzoyl cyclohexene.
6. preparation technology as claimed in claim 1, it is characterized in that, described third product is 2-(4-fluoro benzoyl) pimelinketone.
7. preparation technology as claimed in claim 1, it is characterized in that, in institute's step (3) in described distillation with more comprise after removing described methylene dichloride utilize water content lower than 10% ethanol make described 3rd reaction intermediates crystallization again, filter and obtain described third product after drying.
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| CN201510071703.8A CN104649882A (en) | 2015-02-11 | 2015-02-11 | Intermediate preparation process of phosphodiesterase inhibitor |
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| CN117820198A (en) * | 2023-03-14 | 2024-04-05 | 浙江绿创生物科技有限公司 | Treatment method of waste liquid from enamine synthesis reaction in BA progesterone synthesis process |
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| CN102300860A (en) * | 2008-11-14 | 2011-12-28 | 安姆根有限公司 | Pyrazine compounds as phosphodiesterase 10 inhibitors |
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| GB1484117A (en) * | 1975-03-28 | 1977-08-24 | Anvar | Process for the preparation of carbonyl alpha-perfluoro derivatives |
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| CN117820198A (en) * | 2023-03-14 | 2024-04-05 | 浙江绿创生物科技有限公司 | Treatment method of waste liquid from enamine synthesis reaction in BA progesterone synthesis process |
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