CN103992319A - Pyridine carboxylic acid compounds and preparation method thereof - Google Patents
Pyridine carboxylic acid compounds and preparation method thereof Download PDFInfo
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- CN103992319A CN103992319A CN201410227465.0A CN201410227465A CN103992319A CN 103992319 A CN103992319 A CN 103992319A CN 201410227465 A CN201410227465 A CN 201410227465A CN 103992319 A CN103992319 A CN 103992319A
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- pyridine
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- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- KDGNDVIFEUMRNO-UHFFFAOYSA-N 1h-pyrrolo[3,2-c]pyridine-4-carboxylic acid Chemical compound OC(=O)C1=NC=CC2=C1C=CN2 KDGNDVIFEUMRNO-UHFFFAOYSA-N 0.000 claims abstract description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 6
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims abstract description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 5
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims abstract description 5
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000012467 final product Substances 0.000 claims abstract description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 8
- 229940125773 compound 10 Drugs 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 3
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 230000004224 protection Effects 0.000 claims description 3
- 150000003233 pyrroles Chemical class 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract 2
- 229910019213 POCl3 Inorganic materials 0.000 abstract 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 abstract 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- 239000002994 raw material Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- -1 nitrogen heterocyclic compounds Chemical class 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 101150111783 NTRK1 gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
- 108010030743 Tropomyosin Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 102000017953 prostanoid receptors Human genes 0.000 description 1
- 108050007059 prostanoid receptors Proteins 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 238000005406 washing Methods 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to pyridine carboxylic acid compounds and a preparation method thereof. The compounds are 1H-pyrrolo[3,2-c]pyridine-4-carboxylic acid; the preparation method is as follows: (1), obtaining compounds 2 by Vilsmeier-Haack reaction of pyridine; (2), obtaining compounds 3 by reacting with benzyl chloride; (3), adding malonic acid and piperidine into the compound 3 system to obtain compounds 4; (4), adding ethyl chloroformate and sodium azide aqueous liquor into the compound 4 system to obtain compounds 5; (5), refluxing the compounds 5 in diphenyl ether liquor of tributylamine to obtain compounds 6; (6), refluxing after dissolving the compounds 6 in POCl3 to obtain compounds 7; (7), removing benzyl from the compounds by utilizing potassium tert-butoxide to obtain compounds 8; (8), protecting the compounds 8 with Boc to obtain compounds 9; (9), carrying out carbonyl-inserting reaction on the compounds 9 to obtain compounds 10; (10), alkali-hydrolyzing the compounds 10 to obtain a final product compound 11.
Description
Technical field
The present invention relates to midbody compound production field, especially a kind of pyridine carboxylic acid compounds and preparation method thereof.
Background technology
According to Preparation of fused nitrogen heterocyclic compounds as prostanoid receptor EP1ligands.PCT int.Appl. (2013), the documents such as WO2013037960A120130321 are recorded, pyridine carboxylic acid compounds is extensively present in and has in bioactive natural product and drug molecule, in treatment cancer, cardiovascular and nervous system disorders aspect has huge using value, taking this compound as the synthetic derivative of intermediate, a lot of bioactive compoundss that have been proved to be to be used as kinase whose inhibitor and treat pain.Visible, due to its good pharmacologically active and potential pharmaceutical use, present stage pyridine carboxylic acid compounds synthetic receiving much attention.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of pyridine carboxylic acid compounds.
Another technical problem to be solved by this invention is to provide the preparation method of above-mentioned pyridine carboxylic acid compounds.
For solving the problems of the technologies described above, technical scheme of the present invention is:
A kind of pyridine carboxylic acid compounds, 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid, its structural formula is shown in (I),
Preferably, above-mentioned pyridine carboxylic acid compounds, 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid is white solid, its proton nmr spectra data are 1H-NMR (DMSO; 400MHZ) 7.29 (s, 1H) 7.83 (d, 2H) 8.22 (d, 1H) 12.40 (d, 1H) 8.425 (s, 1H).
The preparation method of above-mentioned pyridine carboxylic acid compounds, concrete steps are as follows:
(1) reaction of compound 1 pyrroles's Wei Er David Smail-Haake obtains compound 2;
(2) obtain compound 3 with compound 2 and benzyl chloride reaction;
(3) in compound 3 systems, add propanedioic acid and piperidines to obtain compound 4;
(4) in compound 4 systems, add Vinyl chloroformate and sodium azide aqueous solution to obtain compound 5;
(5) compound 5 refluxes and obtains compound 6 in the phenyl ether solution of Tributylamine;
(6) compound 6 is dissolved in to POCl
3after, system refluxes and obtains compound 7;
(7) utilize potassium tert.-butoxide that compound 7 is sloughed to benzyl and obtain compound 8;
(8) utilize compound 8 use Boc protections to obtain compound 9;
(9) compound 9 is inserted to carbonyl reaction and obtain compound 10;
(10) alkaline hydrolysis compound 10 obtains final product compound 11, wherein
Preferably, the preparation method of above-mentioned pyridine carboxylic acid compounds, described compound 9, as intermediate product, is new compound.
The preparation method's of above-mentioned pyridine carboxylic acid compounds concrete reaction equation is as follows:
The invention has the beneficial effects as follows:
The preparation method of above-mentioned pyridine carboxylic acid compounds is the preparation method of a kind of raw material cheapness, the simple 1H-pyrrolo-of synthetic method [3,2-c] Pyridine-4-carboxylic acid.
Brief description of the drawings
Fig. 1 is the HNMR spectrogram of 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic 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
The preparation method of 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid, concrete steps are as follows:
(1), by 1.81kg DMF (dimethyl formamide) and 2L1, after 2-ethylene dichloride mixes, under the condition of 5 DEG C, in system, drip lentamente 3.806kg POCl
3after 80min dropwises, under the condition of 5 DEG C, to dropping compound 1 pyrroles 1.512kg slowly again in system; After 30min, dropwise, system returns to stirring at room temperature reaction; After 2h reacts completely, system is joined in 6N aqueous sodium hydroxide solution 15L lentamente to regulator solution PH to 8, suction filtration adds DCM (2L*2) extraction in water, and organic layer merges, after anhydrous sodium sulfate drying, being spin-dried for, obtaining compound 2, is brown oil crude product 2166g.TLC information: raw material Rf=0.5, product Rf=0.4, developping agent: sherwood oil: ethyl acetate=5:1.
(2) 1728g compound 2 is dissolved in after 9L DCM, under room temperature condition, in system, adds 1453gNaOH and the 3.4ml aqueous solution and 170g Tetrabutyl amonium bromide; System is cooled to after 0 DEG C, starts to drip 2520g BnCl, and 1h drips complete, is warming up to 40 DEG C of backflows, stirring reaction; After 15h reacts completely, suction filtration reaction solution, adds DCM (2L*2), extraction, and organic layer merges, and after anhydrous sodium sulfate drying, is spin-dried for, and obtains compound 3, is brown oil crude product 5.25kg.TLC information: raw material Rf=0.4, product Rf=0.5, developping agent: sherwood oil: ethyl acetate=5:1.
(3) 4.1Kg compound 3 is dissolved in after 6.15L pyridine, under room temperature, in system, adds 3.46kg propanedioic acid and 1.64kg piperidines, be warming up to 120 DEG C of backflows, stirring reaction; After 15h reacts completely, after concentration of reaction solution, add wherein 8L3N aqueous hydrochloric acid, regulate PH to 2, separate out solid, suction filtration, ethyl acetate for filter cake (2L) washing, filtrate is abandoned it, obtains compound 4, is crude product brown solid 2.2kg.TLC information: raw material Rf=0.4, product Rf=0.2, developping agent: sherwood oil: ethyl acetate=5:1.
(4) 2.2kg compound 4 is dissolved in to 10L acetone, then adds 2.2L TEA (trolamine), system is cooled to after 5 DEG C, in system, drips 1.58kg Vinyl chloroformate; 30min drips complete, dropwises rear some plate, after TLC shows that raw material reaction completely, then drips the 755g sodium azide 3L aqueous solution in system, and 2h dropwises, and returns to room temperature reaction; After 2h reacts completely, added 5L aqueous sodium carbonate to regulate PH to 8, add dichloromethane extraction twice, organic layer merges, and after anhydrous sodium sulfate drying, is spin-dried for, and obtains compound 5, is brown oil crude product 2.4kg.TLC information: raw material Rf=0.5, product Rf=0.7, developping agent: sherwood oil: ethyl acetate=3:1.
(5) 2L Tributylamine is dissolved in to 4L phenyl ether, system is warming up to 190 DEG C, then drips wherein 1020g compound 5 (a small amount of methylene dichloride), 190 DEG C of return stirring reactions; After 3h reacts completely, system is cooled to 60 DEG C, then adds 5L ethyl acetate solution in system, stirs after 30min, and suction filtration obtains black solid, and filtrate is abandoned it, obtains compound 6, is 440 grams of black solid crude products.TLC information: raw material Rf=0.8, product Rf=0.35, developping agent: methylene dichloride: methyl alcohol=20:1;
(6) 415g compound 6 is dissolved in to 2L POCl
3after, DEG C backflow of system temperature control to 120, stirring reaction; After 17h reacts completely, concentrate system, adds water 500ml by system, adds sodium hydroxide to regulate PH to 8, adds 2L methylene dichloride, suction filtration, and gained organic layer merges, and after anhydrous sodium sulfate drying, is spin-dried for, and obtains crude product 295g; Crude product is crossed post and is obtained compound 7, is yellow solid 159.34g.TLC information: raw material Rf=0.35, product Rf=0.5, developping agent: methylene dichloride: methyl alcohol=10:1.
(7) 168.23g compound 7 is dissolved in after 1.2L THF (tetrahydrofuran (THF)), under room temperature, then in system, adds 777.80g potassium tert.-butoxide successively, 541.6g DMSO (dimethyl sulfoxide (DMSO)), uncovered reaction; After 17h reacts completely, system is added to saturated ammonium chloride solution 4L, add 4L ethyl acetate, separatory, organic layer merges, and after anhydrous sodium sulfate drying, is spin-dried for, and obtains compound 8, is yellow solid crude product 127.68g.TLC information: raw material Rf=0.5, product Rf=0.2, developping agent: sherwood oil: ethyl acetate=3:1.
(8) room temperature, is dissolved in 127.68g compound 8 after 1.3L THF, then in system, adds 10.22g DMAP (DMAP) and 273.95g Boc2O successively; After 3h reacts completely, system is concentrated, and the thick product of gained is crossed silicagel column (200-300 order silica gel), obtains compound 9, and sterling 90.6g is white solid (PE goes out sundry goods, sherwood oil: ethyl acetate=20:1 goes out product).TLC information: raw material Rf=0.3, product Rf=0.7, developping agent: sherwood oil: ethyl acetate=3:1.Eight step overall yields are 6%.
(9) 33g compound 9 is dissolved in after 660ml methyl alcohol, more successively by 26.4g TEA and 0.33gPd (dppf) Cl
2, put into reactor, with CO displacement three times, at 1.4MPa, react at 120 DEG C; After 17h reacts completely, suction filtration is concentrated, obtains compound 10, is brown solid crude product 44g.TLC information: raw material Rf=0.6, product Rf=0.2, developping agent: methylene dichloride: methyl alcohol=10:1.
(10), under room temperature, 44g compound 10 is dissolved in after 440ml methyl alcohol to the aqueous solution that adds 19.8g NaOH and 300ml to be made into, stirring reaction; After 1h reacts completely, concentrate system, adds 100mL water, and suction filtration adds concentrated hydrochloric acid to regulate PH to 1 in water, separate out solid, suction filtration, dry, obtain the finished product 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid (compound 11), be white solid, sterling 19g, two step productive rates are 60%.TLC information: raw material Rf=0.6, product Rf=0.2, developping agent: methylene dichloride: methyl alcohol=10:1.1H-NMR(DMSO；400MHZ)7.29(s,1H)7.83(d,2H)8.22(d,1H)12.40(d,1H)8.425(s,1H)。
Embodiment 1 gained the finished product 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid (compound 11) can be used as intermediate for following building-up reactions:
The LCMS:Rt=1.58min of synthetic final product; M/z426[M+H]+. biological activity (Trka enzyme): (IC50)=496nM, through confirming and Pyrrolo[2,3-d] (PCT Int.Appl. (2012), WO2012137089A120121011 is identical for pyrimidine derivatives as inhibitors of tropomyosin-related kinases and their preparation and use in the treatment of pain.
Above-mentioned detailed description of this kind of pyridine carboxylic acid compounds and preparation method thereof being carried out with reference to embodiment; illustrative instead of determinate; can list several embodiment according to institute's limited range; therefore in the variation and the amendment that do not depart under general plotting of the present invention, within should belonging to protection scope of the present invention.
Claims (4)
1. a pyridine carboxylic acid compounds, is characterized in that: be 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid, its structural formula is shown in (I),
2. pyridine carboxylic acid compounds according to claim 1, is characterized in that: described 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid is white solid, and its proton nmr spectra data are 1H-NMR (DMSO; 400MHZ) 7.29 (s, 1H) 7.83 (d, 2H) 8.22 (d, 1H) 12.40 (d, 1H) 8.425 (s, 1H).
3. the preparation method of pyridine carboxylic acid compounds claimed in claim 1, is characterized in that: concrete steps are as follows:
(1) reaction of compound 1 pyrroles's Wei Er David Smail-Haake obtains compound 2;
(2) obtain compound 3 with compound 2 and benzyl chloride reaction;
(3) in compound 3 systems, add propanedioic acid and piperidines to obtain compound 4;
(4) in compound 4 systems, add Vinyl chloroformate and sodium azide aqueous solution to obtain compound 5;
(5) compound 5 refluxes and obtains compound 6 in the phenyl ether solution of Tributylamine;
(6) compound 6 is dissolved in to POCl
3after, system refluxes and obtains compound 7;
(7) utilize potassium tert.-butoxide that compound 7 is sloughed to benzyl and obtain compound 8;
(8) utilize compound 8 use Boc protections to obtain compound 9;
(9) compound 9 is inserted to carbonyl reaction and obtain compound 10;
(10) alkaline hydrolysis compound 10 obtains final product compound 11, wherein
4. the preparation method of pyridine carboxylic acid compounds according to claim 3, is characterized in that: described compound 9, as intermediate product, is new compound.
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| CN113912533A (en) * | 2021-11-23 | 2022-01-11 | 西安凯立新材料股份有限公司 | Method for preparing 3, 6-dichloropicolinic acid |
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