CN103980139B - Sunaptic acid compounds and preparation method thereof - Google Patents
Sunaptic acid compounds and preparation method thereof Download PDFInfo
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- CN103980139B CN103980139B CN201410231332.0A CN201410231332A CN103980139B CN 103980139 B CN103980139 B CN 103980139B CN 201410231332 A CN201410231332 A CN 201410231332A CN 103980139 B CN103980139 B CN 103980139B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000002253 acid Substances 0.000 title claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical group FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 7
- 229940125898 compound 5 Drugs 0.000 claims abstract description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 3
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 3
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 239000012467 final product Substances 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 150000002790 naphthalenes Chemical class 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 150000005209 naphthoic acids Chemical class 0.000 abstract description 10
- CMRLOYGGEHKCNY-UHFFFAOYSA-N 4-amino-3-methylnaphthalene-2-carboxylic acid Chemical compound C1=CC=C2C=C(C(O)=O)C(C)=C(N)C2=C1 CMRLOYGGEHKCNY-UHFFFAOYSA-N 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- -1 filter Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to sunaptic acid compounds and preparation method thereof, this compound is 4-amino-3-methyl-2-naphthoic acid, preparation method is as follows: (1) for starting raw material, with thionyl chloride and methyl alcohol by carboxylic esterification, obtains compound 2 with compound 13-hydroxy-2-naphthoic acid; (2) compound 2 nitric acid nitro on naphthalene nucleus 4, obtains compound 3; (3) compound 3 Trifluoromethanesulfonic anhydride substituted hydroxy makes compound 4; (4) compound 4 obtains compound 5 by Suzuki coupling; (5) nitroreduction is become amino by compound 5 palladium carbon, obtains compound 6; (6) Ester hydrolysis is obtained final product compound 7 by compound 6 in the basic conditions; This preparation method's raw material is cheaply easy to get, and route overall yield is higher, is a kind of method of brand-new synthesis naphthoic acid derivative, is applicable to the needs that large-scale industrial is produced.
Description
Technical field
The present invention relates to production of chemicals field, especially sunaptic acid compounds and preparation method thereof.
Background technology
Naphthoic acid compounds is extensively present in and has in bioactive natural product and drug molecule, and being important pharmaceutical compound, is also the compounds that current new drug development field is shown great attention to.The pharmacologically active good due to it and potential pharmaceutical use, the synthesis of naphthoic acid derivative receives much attention.Doing parent with this compound can carry out further synthesizing more complicated derivative, providing condition for broadly studying such compound property.
Summary of the invention
Technical problem to be solved by this invention is to provide sunaptic acid compounds.
Another technical problem to be solved by this invention is the preparation method providing above-mentioned naphthoic acid compounds.
For solving the problems of the technologies described above, technical scheme of the present invention is:
Sunaptic acid compounds, 4-amino-3-methyl-2-naphthoic acid, its structural formula for shown in (I),
Preferably, above-mentioned naphthoic acid compounds, 4-amino-3-methyl-2-naphthoic acid is pale solid, and its hydrogen nuclear magnetic resonance modal data is 1H-NMR (DMSO; 400HZ) 2.509 (s, 3H) 7.507 (m, 1H) 7.581 (t, 1H) 7.846 (s, 1H) 7.924 (d, 1H) 8.230 (d, 1H).
The preparation method of above-mentioned naphthoic acid compounds, concrete steps are as follows:
(1) with compound 13-hydroxy-2-naphthoic acid for starting raw material, with thionyl chloride and methyl alcohol by carboxylic esterification, obtain compound 2;
(2) compound 2 nitric acid nitro on naphthalene nucleus 4, obtains compound 3;
(3) compound 3 Trifluoromethanesulfonic anhydride substituted hydroxy makes compound 4;
(4) compound 4 obtains compound 5 by Suzuki coupling;
(5) nitroreduction is become amino by compound 5 palladium carbon, obtains compound 6;
(6) Ester hydrolysis is obtained final product compound 7 by compound 6 in the basic conditions, wherein,
Preferably, the preparation method of above-mentioned naphthoic acid compounds, described compound 3,4,5,6, as intermediate product, is new compound.
The concrete reaction equation of the preparation method of above-mentioned naphthoic acid compounds is as follows:
The invention has the beneficial effects as follows:
The preparation method of above-mentioned naphthoic acid compounds, raw material is cheaply easy to get, and route overall yield is higher, is a kind of method of brand-new synthesis naphthoic acid derivative, is applicable to the needs that large-scale industrial is produced.
Accompanying drawing explanation
Fig. 1 is the HNMR spectrogram of 4-amino-3-methyl-2-naphthoic acid.
Embodiment
In order to make those skilled in the art better understand technical scheme of the present invention, below in conjunction with embodiment, technical scheme of the present invention is described in further detail.
Embodiment 1
As shown in Figure 1, the preparation method of 4-amino-3-methyl-2-naphthoic acid, concrete steps are as follows:
(1) in 1L there-necked flask, 50g compound 1 (3-hydroxy-2-naphthoic acid) is dissolved in 190mL methylene dichloride (DCM) and 190mL methyl alcohol (MeOH), again 41mL thionyl chloride is slowly instilled above-mentioned system, control temperature is no more than 40 DEG C, 40min dropwises, then by system temperature rising reflux reaction overnight.React complete after 14h, revolve steaming and desolventize, saturated sodium bicarbonate solution adjusts PH=7,500mL extraction into ethyl acetate twice, and organic phase drying concentrates to obtain product (compound 2) 53g, yield 98%.TLC information (methylene dichloride: methyl alcohol=5:1): raw material Rf=0.2, product Rf=0.8.1H-NMR(CDCl
3；400HZ)4.002(s,3H)7.290(m,1H)7.478(t,1H)7.664(d,1H)7.774(d,1H)8.642(s,1H)10.410(s,1H)
(2) 48g compound 2 is dissolved in 500mL methylene dichloride, be cooled to 0 DEG C, slowly instill 41g nitric acid, 1h dropwises, and question response is complete, system is poured in frozen water, filter, filter cake dries to obtain product 20g, and disposing mother liquor obtains product (compound 3) 6g, 26g altogether, yield 41%.TLC information (sherwood oil: ethyl acetate=3:1): raw material Rf=0.7, product Rf=0.5.
(3) in 1L there-necked flask, add 24.6g compound 3,15.8g pyridine and 250mL anhydrous methylene chloride successively, system is cooled to 0 DEG C, slowly drip the Trifluoromethanesulfonic anhydride of 1.0 equivalents, 30min drips complete, and question response is complete, reacts with saturated sodium bicarbonate solution cancellation, separate organic phase, with saturated nacl aqueous solution washing, then wash with 3N hydrochloric acid soln, the drying of gained organic phase is concentrated to obtain crude product (compound 4) 38.1g.TLC information (sherwood oil: ethyl acetate=3:1): raw material Rf=0.5, product Rf=0.7.
(4) in 1L there-necked flask, 38.1g compound 4,42.6g potassiumphosphate is added successively, 11.8g methyl-boron-dihydroxide, 3.81g Pd (dppf) Cl
2and the tetrahydrofuran (THF) of 400mL drying, then use argon replaces 3 times, be warming up to 65 DEG C of back flow reaction.React completely after 4h, revolve and steam removing THF, residuum saturated sodium bicarbonate solution washs, add 500mL EA (ethyl acetate) again, with diatomite filtration, which floor filtrate separated, aqueous phase uses 300mL extraction into ethyl acetate once again, merge organic phase, dry concentrated silicagel column (500 grams of 200-300 order silicon gel column) obtains sterling (compound 5) 21.5g, two step yields 88.1%.TLC information (sherwood oil: ethyl acetate=5:1): raw material Rf=0.5, product Rf=0.7.
1H-NMR(CDCl
3；400HZ)2.553(s,3H)3.898(s,3H)7.496(d,1H)7.531(d,1H)7.600(t,1H)7.849(d,1H)8.465(s,1H)
(5) in 500mL single port bottle, 19g compound 5,2g palladium carbon and 190mL methyl alcohol is added, hydrogen exchange, and ambient temperature overnight reaction under 0.15M Pa.14h reaction is complete, and in system, add ethyl acetate make it clearly molten, diatomite filtration, filtrate is spin-dried for obtain crude product (compound 6) 16.5g.TLC information (sherwood oil: ethyl acetate=3:1): raw material Rf=0.8, product Rf=0.4.1H-NMR(CDCl
3；400HZ)2.493(s,3H)3.941(s,3H)4.260(s,2H)7.442(m,1H)7.526(m,1H)7.773(s,1H)7.799(d,1H)
(6) in 1L single port bottle, 16.5g compound 6,11.2g sodium hydroxide is added, and 150mL methyl alcohol and 150mL water, be then warming up to 50 DEG C of stirring reactions.1.5h reaction is complete, revolves and steams removing methyl alcohol, after aqueous phase is extracted with ethyl acetate, then adjust PH=4 with HCl, separate out product, filter, filter cake methyl tertiary butyl ether (MTBE) making beating washing, dries, obtain sterling (compound 7) 15g, pale solid, two step yields 96.2%.TLC information (sherwood oil: ethyl acetate=3:1): raw material Rf=0.4, product Rf=0.2.1H-NMR(DMSO；400HZ)2.509(s,3H)7.507(m,1H)7.581(t,1H)7.846(s,1H)7.924(d,1H)8.230(d,1H)
Application test example
Example 1 gained compound 20mg is dissolved in 5ml methocel solution as test soln.
Get 14 weeks male mouses 6, oral test soln, 5mg/kg, after 30 minutes, continue oral 0.2ml contain 2 μ Ci [
3h] INERALIPID of-cholesterol/mouse
tM, to euthanizing animals after five hours, and collect liver and blood.Measure the cholesterol amount in liver and blood plasma, cholesterol absorption suppresses per-cent to be about 82%.
Above-mentioned detailed description of this sunaptic acid compounds and preparation method thereof being carried out with reference to embodiment; illustrative instead of determinate; several embodiments can be listed according to institute's limited range; therefore in the change do not departed under general plotting of the present invention and amendment, should belong within protection scope of the present invention.
Claims (1)
1. the preparation method of sunaptic acid compounds, is characterized in that: concrete steps are as follows:
(1) with compound 13-hydroxy-2-naphthoic acid for starting raw material, with thionyl chloride and methyl alcohol by carboxylic esterification, obtain compound 2;
(2) compound 2 nitric acid nitro on naphthalene nucleus 4, obtains compound 3;
(3) compound 3 Trifluoromethanesulfonic anhydride substituted hydroxy makes compound 4;
(4) compound 4 obtains compound 5 by Suzuki coupling;
(5) nitroreduction is become amino by compound 5 palladium carbon, obtains compound 6;
(6) Ester hydrolysis is obtained final product compound 7 by compound 6 in the basic conditions, and wherein the structural formula of compound 1 to 7 is as follows,
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Denomination of invention: Naphthenic acid compound and its preparation method Effective date of registration: 20220525 Granted publication date: 20150916 Pledgee: Tianjin Binhai rural commercial bank Limited by Share Ltd. Pledgor: SPHINX SCIENTIFIC LABORATORY (TIANJIN) CO.,LTD. Registration number: Y2022120000023 |
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Date of cancellation: 20230612 Granted publication date: 20150916 Pledgee: Tianjin Binhai rural commercial bank Limited by Share Ltd. Pledgor: SPHINX SCIENTIFIC LABORATORY (TIANJIN) CO.,LTD. Registration number: Y2022120000023 |
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Denomination of invention: A Naphthalic Acid Compound and Its Preparation Method Effective date of registration: 20230703 Granted publication date: 20150916 Pledgee: Tianjin Binhai rural commercial bank Limited by Share Ltd. Pledgor: SPHINX SCIENTIFIC LABORATORY (TIANJIN) CO.,LTD. Registration number: Y2023120000052 |