CN115557883A - Synthesis process of amlodipine - Google Patents
Synthesis process of amlodipine Download PDFInfo
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- CN115557883A CN115557883A CN202211337708.7A CN202211337708A CN115557883A CN 115557883 A CN115557883 A CN 115557883A CN 202211337708 A CN202211337708 A CN 202211337708A CN 115557883 A CN115557883 A CN 115557883A
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 28
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 24
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 24
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000003446 ligand Substances 0.000 claims abstract description 15
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 18
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 11
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 11
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 11
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 11
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 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 description 4
- 239000012445 acidic reagent Substances 0.000 claims description 4
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- IZWRXCGNSVOSAT-UHFFFAOYSA-L dichloronickel;diphenyl(propyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 IZWRXCGNSVOSAT-UHFFFAOYSA-L 0.000 claims description 3
- XXECWTBMGGXMKP-UHFFFAOYSA-L dichloronickel;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XXECWTBMGGXMKP-UHFFFAOYSA-L 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 abstract description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000005557 antagonist Substances 0.000 abstract description 3
- 229910001424 calcium ion Inorganic materials 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract description 2
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 17
- 238000005406 washing Methods 0.000 description 17
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- MPEOPBCQHNWNFB-UHFFFAOYSA-N 1-chloro-2-iodobenzene Chemical compound ClC1=CC=CC=C1I MPEOPBCQHNWNFB-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003445 Hantzsch reaction Methods 0.000 description 5
- 230000007547 defect Effects 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- RLKBOGLIOLFMEK-NSCUHMNNSA-N amino (e)-but-2-enoate Chemical compound C\C=C\C(=O)ON RLKBOGLIOLFMEK-NSCUHMNNSA-N 0.000 description 1
- 229960004005 amlodipine besylate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- XLGLMVCAOMQNJT-UHFFFAOYSA-N boric acid;chlorobenzene Chemical compound OB(O)O.ClC1=CC=CC=C1 XLGLMVCAOMQNJT-UHFFFAOYSA-N 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthesis process of amlodipine, which is a synthesis process of amlodipine with high atom economy, and particularly comprises the steps of firstly activating a carbon-hydrogen bond of a 1, 4-dihydropyridine derivative through the participation of a nickel catalyst, a metal salt catalyst and a ligand, and reacting the activated carbon-hydrogen bond with o-iodobenzene to construct a new carbon-carbon bond, so that a target product is generated in situ; the method has the advantages of safe and controllable raw materials, mild reaction, convenient operation, low cost, high yield and high purity of the product, is more suitable for industrial production of amlodipine and provides a new idea for preparing other dihydropyridine calcium ion antagonists.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a synthesis process of amlodipine.
Background
Amlodipine is a long-acting calcium ion antagonist, is clinically used for treating hypertension and angina, has very important application in the field of cardiovascular and cerebrovascular diseases, and has the following chemical structural formula:
amlodipine is the first choice drug for treating hypertension at present, shows good bioavailability and longer half-life in vivo, and has slower speed of combination and dissociation with receptors, so that the drug action is delayed and longer in maintenance time, has large selective action on vascular smooth muscle, and shows good pharmacological activity on heart diseases such as hypertension.
Korean patent No. 87-909 discloses a synthesis process of amlodipine, which comprises the steps of performing Hantzsch reaction on azide, aminocrotonate and 2-chlorobenzaldehyde to obtain a 1, 4-dihydropyridine derivative, and reducing the azide to amlodipine, wherein the synthesis process comprises the following steps:
the disadvantages of this process are that the yield is only 19% and that the danger of azides is high and it is not suitable for large scale production.
Korean patent No. 87-909 further discloses a synthesis process of amlodipine, which specifically uses a derivative in which an amino group is protected by two benzyl groups to perform Hantzsch reaction, and then removes the benzyl groups, wherein the route is as follows:
the method has the defects of lower yield of only about 10 percent, the problem of removing benzyl by two steps of hydrogenation, complicated steps, high post-treatment difficulty and limitation on the improvement of the product yield.
U.S. Pat. No. 5,654 discloses a synthesis process of amlodipine besylate, specifically using derivatives of which amino group is protected by triphenylmethyl to carry out Hantzsch reaction, and then removing protecting group by benzenesulfonic acid treatment, the route is as follows:
the method has the defects that the yield is extremely low and is only 7%, the removal of trityl causes troublesome post-treatment, the atom economy is poor, and the method cannot be suitable for the industrial production of amlodipine.
At present, various methods for synthesizing amlodipine have been published and reported, the problem of too low yield of the Hantzsch reaction often exists, the process of removing a protecting group is complicated, the yield is not improved, and the reaction steps and the process cost are further increased. In view of the defects of the prior art, the development of an amlodipine synthesis route with simple steps, mild reaction, satisfactory yield and controllable cost is needed to meet the industrial preparation of the product.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a synthesis process of amlodipine.
The technical scheme for solving the technical problems is as follows:
the invention discloses an amlodipine synthesis process, which comprises the following steps:
(1) Dissolving a compound of a formula I and a compound of a formula II in a reaction solvent, adding a nickel catalyst, a ligand, an alkaline reagent, a metal salt catalyst and water, and reacting under the protection of nitrogen to obtain a compound of a formula III;
(2) The compound of the formula III is subjected to Boc removal reaction under the action of an acidic reagent to obtain a compound of a formula IV, namely a target product;
the specific reaction route is as follows:
further, the molar ratio of the compound of formula I to the compound of formula II in the step (1) is 1;
further, the nickel catalyst in the step (1) is selected from nickel acetylacetonate, 1, 2-bis (diphenylphosphino) ethane nickel dichloride, 1, 3-bis (diphenylphosphinopropane) nickel dichloride or 1,1' -bis (diphenylphosphino) ferrocene nickel dichloride, and the molar amount of the nickel catalyst is 5-15%, preferably 10-15% of that of the compound shown in the formula I;
further, the ligand in the step (1) is a quinoline derivative; the molar amount of the ligand is 10-20%, preferably 15-20% of that of the compound shown in the formula I; the structural formula is as follows:
further, the alkaline reagent in the step (1) is selected from disodium hydrogen phosphate or dipotassium hydrogen phosphate, preferably disodium hydrogen phosphate; the molar ratio of the compound of formula I to the basic agent is 1.5 to 3, preferably 1;
further, the metal salt catalyst in the step (1) is selected from silver carbonate or silver acetate, preferably silver carbonate; the molar ratio of the compound of formula I to the metal salt catalyst is 1;
further, the reaction solvent in the step (1) is n-propanol;
further, the molar ratio of the compound of formula I to water in step (1) is 1;
further, the reaction temperature of the step (1) is 80-100 ℃, preferably 90-100 ℃; the reaction time is 20 to 30 hours, preferably 24 to 26 hours;
further, the acidic reagent in the step (2) is selected from a dioxane hydrochloride solution;
further, the reaction solvent of step (2) is selected from dioxane;
further, the reaction temperature of the step (2) is 10-30 ℃, and preferably 20-30 ℃; the reaction time is 4 to 6 hours, preferably 4 to 5 hours;
further, the step (2) further comprises adding a proper amount of alkaline solution into the obtained product after the reaction is finished to adjust the pH value to be alkalescent so as to obtain a compound shown in the formula IV;
further, the alkaline solution is selected from one or more of saturated sodium bicarbonate solution, saturated sodium carbonate solution or saturated potassium bicarbonate solution, and preferably saturated sodium bicarbonate solution.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for a significant error in the formula.
The invention has the beneficial effects that:
(1) The invention adopts a brand new synthesis strategy, and the 1, 4-dihydropyridine derivative is activated by a carbon-hydrogen bond and reacts with o-chlorobenzene borate to construct a new carbon-carbon bond, thereby replacing the traditional Hantzsch reaction and generating a target product in situ, and the synthesis process of the amlodipine with high atom economy is provided;
(2) The raw materials used in the method are safe and controllable, the reaction is mild, the operation is convenient, the cost is low, the product has high yield and high purity, the green chemical concept is met, and the method is more suitable for the industrial production of amlodipine;
(3) The method for constructing the new C-C bond also provides a new idea for preparing other dihydropyridine calcium ion antagonists.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
(1) 10g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 0.5g of nickel acetylacetonate Ni (acac) 2 1.3g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-propanol are added into a 250ml reaction bottle, the mixture is heated to 95 ℃ under the protection of nitrogen, reflux reaction is carried out for 25 hours, and TLC detects that the raw materials are completely converted. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 10.37g of light yellow solid with the yield of 85%.
(2) And (3) adding 5g of the compound of the formula III obtained in the previous step into a 100mL reaction bottle, adding 30mL of dioxane, stirring to dissolve the mixture clearly, controlling the temperature to be 5-10 ℃, dropwise adding 8mL of dioxane hydrochloride solution (the concentration is 2M) into the reaction bottle, slowly heating to 25-30 ℃ after dropwise adding, reacting for 4 hours, and monitoring the disappearance of the raw materials by TLC. Concentrating the reaction solution to dryness, adding 30ml of dichloromethane, stirring and dispersing, adjusting the pH to 8-9 by using a saturated sodium bicarbonate solution, standing and layering, washing a water layer twice by using dichloromethane, combining organic phases, drying and concentrating to obtain 3.18 yellow solid with the yield of 95% and the purity of 99.2%.
1 H NMR(500MHz,CDCl 3 )：δ7.36–7.20(m,3H),7.13(td,J＝7.4,2.2Hz,1H),5.31(dd,J＝2.1,1.2Hz,1H),4.65(dd,J＝12.3,1.0Hz,1H),4.49(dd,J＝12.3,1.0Hz,1H),4.40(dq,J＝12.5,8.0Hz,1H),3.94(dq,J＝12.3,7.9Hz,1H),3.57(ddd,J＝12.5,11.2,3.8Hz,1H),3.48(ddd,J＝12.2,11.1,3.8Hz,1H),3.44(s,3H),3.05(m,2H),2.30(d,J＝1.1Hz,3H),1.27(t,J＝8.0Hz,3H),1.10(s,2H).
MS(ESI+):m/z 409.88[M+H] + 。
Example 2:
(1) 10g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 0.75g of nickel acetylacetonate Ni (acac) 2 1.3g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-propanol are added into a 250ml reaction bottle, the mixture is heated to 95 ℃ under the protection of nitrogen, reflux reaction is carried out for 25 hours, and TLC detects that the raw materials are completely converted. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 11.23g of light yellow solid with the yield of 92%.
Example 3:
(1) 10g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 0.75g of acetylacetoneNickel Ni (acac) 2 0.975g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-propanol are added into a 250ml reaction bottle, the mixture is heated to 95 ℃ under the protection of nitrogen, reflux reaction is carried out for 25 hours, and TLC detects that the raw materials are completely converted. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 10.74g of light yellow solid with the yield of 88%.
Example 4:
(1) 12g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 0.75g of nickel acetylacetonate Ni (acac) 2 0.975g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-propanol are added into a 250ml reaction bottle, the mixture is heated to 95 ℃ under the protection of nitrogen, reflux reaction is carried out for 25 hours, and TLC detects that the raw materials are completely converted. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 10.73g of light yellow solid with the yield of 88%.
Example 5:
(1) 10g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 1.54g of 1, 2-bis (diphenylphosphino) ethane, nickel dichloride NiCl 2 (dppe), 1.3g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-propanol were added to a 250ml reaction flask, heated to 95 ℃ under nitrogen protection, reacted under reflux for 25 hours, and the TLC detected complete conversion of the starting materials. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 10.50g of light yellow solid with the yield of 86%.
Example 6:
(1) 10g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 1.58g of 1, 3-bis (diphenylphosphinopropane) nickel dichloride NiCl 2 (dppp), 1.3g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-propanol were added into a 250ml reaction flask, heated to 95 ℃ under the protection of nitrogen, refluxed for 25 hours, and subjected to TLC detection to complete conversion of the raw materials. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 10.62g of light yellow solid with the yield of 87%.
Example 7:
(1) 10g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 1.97g of 1,1' -bis (diphenylphosphino) ferrocene, nickel dichloride NiCl 2 (dppf), 1.3g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-propanol are added into a 250ml reaction bottle, heated to 95 ℃ under the protection of nitrogen, subjected to reflux reaction for 25 hours, and subjected to TLC detection to complete conversion of the raw materials. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 10.25g of light yellow solid with the yield of 84%.
Example 8:
(1) 10g of the compound of the formula I, 11.96g of the compound of the formula II (o-chloroiodobenzene), 0.75g of nickel acetylacetonate Ni (acac) 2 1.3g of ligand, 11g of silver carbonate, 5.7g of disodium hydrogen phosphate, 2.5ml of water and 100ml of n-amyl alcohol are added into a 250ml reaction bottle, the mixture is heated to 95 ℃ under the protection of nitrogen, reflux reaction is carried out for 25 hours, and TLC detects that the raw materials are completely converted. After the reaction is finished, adding ethyl acetate to dissolve and disperse, filtering the solution by using kieselguhr, washing a filter cake by using a small amount of ethyl acetate, adding a certain amount of water into the obtained filtrate, extracting and layering, washing an obtained water layer twice by using ethyl acetate, combining organic phases, drying and concentrating, and separating the obtained crude product by using a column to obtain 9.98g of a pale yellow solid, yield 82%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. The synthesis process of amlodipine is characterized by comprising the following steps of:
(1) Dissolving a compound of a formula I and a compound of a formula II in a reaction solvent, adding a nickel catalyst, a ligand, an alkaline reagent, a metal salt catalyst and water, and reacting under the protection of nitrogen to obtain a compound of a formula III;
(2) The compound of the formula III is subjected to Boc removal reaction under the action of an acidic reagent to obtain a compound of a formula IV, namely a target product;
the specific reaction route is as follows:
2. the process for synthesizing amlodipine according to claim 1, wherein the molar ratio of the compound of formula i to the compound of formula ii in step (1) is 1.
3. The synthesis process of amlodipine according to claim 1, wherein the nickel catalyst in step (1) is selected from nickel acetylacetonate, 1, 2-bis (diphenylphosphino) ethane nickel dichloride, 1, 3-bis (diphenylphosphinopropane) nickel dichloride or 1,1' -bis (diphenylphosphino) ferrocene nickel dichloride, and the molar amount of the nickel catalyst is 5-15% of that of the compound of formula I.
4. The synthesis process of amlodipine according to claim 1, wherein the ligand in step (1) is a quinoline derivative; the molar dosage of the ligand is 10-20% of that of the compound shown in the formula I; the structural formula is as follows:
5. the synthesis process of amlodipine according to claim 1, wherein the alkaline agent in step (1) is selected from disodium hydrogen phosphate or dipotassium hydrogen phosphate, and the molar ratio of the compound of formula I to the alkaline agent is 1.5-3.
6. The synthesis process of amlodipine according to claim 1, wherein the metal salt catalyst in step (1) is selected from silver carbonate or silver acetate, and the molar ratio of the compound of formula I to the metal salt catalyst is 1-4.
7. The synthesis process of amlodipine according to claim 1, wherein the reaction solvent of step (1) is n-propanol; the molar ratio of the compound of formula I to water is 1.
8. The synthesis process of amlodipine according to claim 1, wherein the reaction temperature in step (1) is 80-100 ℃ and the reaction time is 20-30 h.
9. The synthesis process of amlodipine according to claim 1, wherein the acidic reagent in step (2) is selected from dioxane hydrochloride solution; the reaction solvent is selected from dioxane.
10. The synthesis process of amlodipine according to claim 1, wherein the reaction temperature in step (2) is 10-30 ℃ and the reaction time is 4-6 h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4515799A (en) * | 1983-02-02 | 1985-05-07 | Pfizer Inc. | Dihydropyridine anti-ischaemic and antihypertensive agents |
| US4568677A (en) * | 1983-07-23 | 1986-02-04 | Pfizer Inc. | 2-(4-Pyrimidone alkoxyalkyl) dihydropyridine anti-ischaemic and antihypertensive agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4515799A (en) * | 1983-02-02 | 1985-05-07 | Pfizer Inc. | Dihydropyridine anti-ischaemic and antihypertensive agents |
| US4568677A (en) * | 1983-07-23 | 1986-02-04 | Pfizer Inc. | 2-(4-Pyrimidone alkoxyalkyl) dihydropyridine anti-ischaemic and antihypertensive agents |
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