CN103992319B - A kind of preparation method of pyridine carboxylic acid compounds - Google Patents
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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 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000000243 solution Substances 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
- 229940125773 compound 10 Drugs 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- 229940125898 compound 5 Drugs 0.000 claims abstract description 8
- 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 abstract description 8
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 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
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims abstract description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims abstract description 4
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims abstract description 4
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000012467 final product Substances 0.000 claims abstract description 4
- 150000003053 piperidines Chemical class 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
- 150000003233 pyrroles Chemical class 0.000 claims abstract description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 3
- 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 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 abstract description 8
- 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
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000002994 raw material Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 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
- 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
- 239000012043 crude product Substances 0.000 description 6
- 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
- 239000012141 concentrate Substances 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
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 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
- 238000003786 synthesis reaction Methods 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
- 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 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
- 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000013067 intermediate product 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 239000007858 starting material Substances 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to a kind of pyridine carboxylic acid compounds and preparation method thereof, this compound is 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid, and preparation method is as follows: the Wei Er David Smail-Haake of (1) pyrroles is obtained by reacting compound 2; (2) and benzyl chloride be obtained by reacting compound 3; (3) in compound 3 system, propanedioic acid is added and piperidines obtains compound 4; (4) Vinyl chloroformate is added in compound 4 system and sodium azide aqueous solution obtains compound 5; (5) compound 5 refluxes and obtains compound 6 in the phenyl ether solution of Tributylamine; (6) compound 6 is dissolved in POCl
3after, system backflow obtains compound 7; (7) utilize potassium tert.-butoxide that compound 7 is sloughed benzyl and obtain compound 8; (8) utilize compound 8 Boc to protect and obtain compound 9; (9) slotting carbonyl is carried out to compound 9 and be obtained by reacting compound 10; (10) alkaline hydrolysis compound 10 obtains 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, at Therapeutic cancer, cardiovascular and nervous system disorders aspect has huge using value, with the derivative that this compound synthesizes for intermediate, much be proved to be can be used as kinase whose inhibitor to treat the bioactive compounds of pain.Visible, the pharmacologically active good due to it and potential pharmaceutical use, the present stage synthesis of pyridine carboxylic acid compounds receives 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 the preparation method providing 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 for shown in (I),
Preferably, above-mentioned pyridine carboxylic acid compounds, 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid is white solid, and its hydrogen nuclear magnetic resonance modal data is 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) the Wei Er David Smail-Haake of compound 1 pyrroles is obtained by reacting compound 2;
(2) compound 3 is obtained by reacting with compound 2 and benzyl chloride;
(3) in compound 3 system, propanedioic acid is added and piperidines obtains compound 4;
(4) Vinyl chloroformate is added in compound 4 system and sodium azide aqueous solution obtains compound 5;
(5) compound 5 refluxes and obtains compound 6 in the phenyl ether solution of Tributylamine;
(6) compound 6 is dissolved in POCl
3after, system backflow obtains compound 7;
(7) utilize potassium tert.-butoxide that compound 7 is sloughed benzyl and obtain compound 8;
(8) utilize compound 8 Boc to protect and obtain compound 9;
(9) slotting carbonyl is carried out to compound 9 and be obtained by reacting 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 concrete reaction equation of the preparation method of above-mentioned pyridine carboxylic acid compounds 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 cheaper starting materials, synthetic method simple 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid.
Accompanying drawing explanation
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) after 1.81kg DMF (dimethyl formamide) and 2L1,2-ethylene dichloride being mixed, under the condition of 5 DEG C, in system, 3.806kg POCl is dripped lentamente
3after 80min dropwises, under the condition of 5 DEG C, dropping compound 1 pyrroles 1.512kg slowly again in system; Dropwise after 30min, system returns to stirring at room temperature reaction; After 2h reacts completely, system is joined lentamente in 6N aqueous sodium hydroxide solution 15L, regulator solution PH to 8, suction filtration, in aqueous phase, add DCM (2L*2) extraction, organic layer merges, being spin-dried for after anhydrous sodium sulfate drying, obtaining compound 2, is crude brown oil 2166g.TLC information: raw material Rf=0.5, product Rf=0.4, developping agent: sherwood oil: ethyl acetate=5:1.
(2), after 1728g compound 2 being dissolved in 9L DCM, under room temperature condition, in system, 1453gNaOH and the 3.4ml aqueous solution and 170g Tetrabutyl amonium bromide is added; After system is cooled to 0 DEG C, start to drip 2520g BnCl, 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 being spin-dried for after anhydrous sodium sulfate drying, obtaining compound 3, is crude brown oil 5.25kg.TLC information: raw material Rf=0.4, product Rf=0.5, developping agent: sherwood oil: ethyl acetate=5:1.
(3) after 4.1Kg compound 3 being dissolved in 6.15L pyridine, under room temperature, in system, add 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 8L3N aqueous hydrochloric acid wherein, regulate PH to 2, separate out solid, suction filtration, filter cake ethyl acetate (2L) washing, filtrate abandons 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 10L acetone, then adds 2.2L TEA (trolamine), after system is cooled to 5 DEG C, in system, drip 1.58kg Vinyl chloroformate; 30min drips complete, dropwises rear some plate, and after TLC display raw material reaction is complete, then in system, drip the 755g sodium azide 3L aqueous solution, 2h dropwises, and returns to room temperature reaction; After 2h reacts completely, added 5L aqueous sodium carbonate and regulate PH to 8, add dichloromethane extraction twice, organic layer merges, and being spin-dried for after anhydrous sodium sulfate drying, obtaining compound 5, is crude brown oil 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 4L phenyl ether, system is warming up to 190 DEG C, then drips 1020g compound 5 (a small amount of methylene dichloride) wherein, 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, and after stirring 30min, suction filtration obtains black solid, and filtrate abandons it, obtains compound 6, is black solid crude product 440 grams.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 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, and add sodium hydroxide and regulate PH to 8, add 2L methylene dichloride, suction filtration, gained organic layer merges, and is spin-dried for, obtains crude product 295g after anhydrous sodium sulfate drying; 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) after 168.23g compound 7 being dissolved in 1.2L THF (tetrahydrofuran (THF)), under room temperature, then in system, 777.80g potassium tert.-butoxide is added successively, 541.6g DMSO (dimethyl sulfoxide (DMSO)), uncovered reaction; After 17h reacts completely, system is added saturated ammonium chloride solution 4L, add 4L ethyl acetate, separatory, organic layer merges, and being spin-dried for after anhydrous sodium sulfate drying, obtaining 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, after 127.68g compound 8 is dissolved in 1.3L THF, then adds 10.22g DMAP (DMAP) and 273.95g Boc2O successively in system; After 3h reacts completely, system concentrates, and the thick product of gained crosses silicagel column (200-300 order silica gel), obtains compound 9, 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) after 33g compound 9 being dissolved in 660ml methyl alcohol, more successively by 26.4g TEA and 0.33gPd (dppf) Cl
2, put into reactor, replace three times with CO, at 1.4MPa, react at 120 DEG C; After 17h reacts completely, suction filtration concentrates, and obtaining 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, after 44g compound 10 is dissolved in 440ml methyl alcohol, the aqueous solution that 19.8g NaOH and 300ml is made into is added, stirring reaction; After 1h reacts completely, concentrate system, adds 100mL water, suction filtration, in aqueous phase, add concentrated hydrochloric acid regulate PH to 1, separate out solid, suction filtration, dry, obtaining the finished product 1H-pyrrolo-[3,2-c] Pyridine-4-carboxylic acid (compound 11), is 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 synthesis 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; 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. a preparation method for pyridine carboxylic acid compounds, is characterized in that: concrete steps are as follows:
(1) the Wei Er David Smail-Haake of compound 1 pyrroles is obtained by reacting compound 2;
(2) compound 3 is obtained by reacting with compound 2 and benzyl chloride;
(3) in compound 3 system, propanedioic acid is added and piperidines obtains compound 4;
(4) Vinyl chloroformate is added in compound 4 system and sodium azide aqueous solution obtains compound 5;
(5) compound 5 refluxes and obtains compound 6 in the phenyl ether solution of Tributylamine;
(6) compound 6 is dissolved in POCl
3after, system backflow obtains compound 7;
(7) utilize potassium tert.-butoxide that compound 7 is sloughed benzyl and obtain compound 8;
(8) utilize compound 8 Boc to protect and obtain compound 9;
(9) slotting carbonyl is carried out to compound 9 and be obtained by reacting compound 10;
(10) alkaline hydrolysis compound 10 obtains final product compound 11, wherein
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| CN113912533B (en) * | 2021-11-23 | 2023-06-20 | 西安凯立新材料股份有限公司 | Method for preparing 3, 6-dichloropicolinic acid |
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