CN110467612A - A kind of simple and convenient process for preparing of prostaglandin D 2 receptor inhibitor compound - Google Patents
A kind of simple and convenient process for preparing of prostaglandin D 2 receptor inhibitor compound Download PDFInfo
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- CN110467612A CN110467612A CN201810438184.8A CN201810438184A CN110467612A CN 110467612 A CN110467612 A CN 110467612A CN 201810438184 A CN201810438184 A CN 201810438184A CN 110467612 A CN110467612 A CN 110467612A
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- prostaglandin
- receptor inhibitor
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 65
- 239000003112 inhibitor Substances 0.000 title claims abstract description 18
- 102000009389 Prostaglandin D receptors Human genes 0.000 title claims abstract description 17
- 108050000258 Prostaglandin D receptors Proteins 0.000 title claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 title abstract description 10
- GFPPXZDRVCSVNR-UHFFFAOYSA-N 2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridin-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC=CN=C2N1CC1=CC=C(S(C)(=O)=O)C=C1C(F)(F)F GFPPXZDRVCSVNR-UHFFFAOYSA-N 0.000 claims abstract description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229950003562 fevipiprant Drugs 0.000 claims abstract description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 230000007062 hydrolysis Effects 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 12
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000007259 addition reaction Methods 0.000 claims abstract description 9
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- -1 2- bromopropene aldehyde Chemical class 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 230000020477 pH reduction Effects 0.000 claims description 9
- 239000003377 acid catalyst Substances 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 5
- 230000005494 condensation Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- ZWHANXMMZRUTAY-UHFFFAOYSA-N 2-chloroprop-2-enal Chemical group ClC(=C)C=O ZWHANXMMZRUTAY-UHFFFAOYSA-N 0.000 claims description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 239000007848 Bronsted acid Substances 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 229950002366 nafoxidine Drugs 0.000 claims description 2
- 150000003053 piperidines Chemical group 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- 239000000243 solution Substances 0.000 claims 2
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- JDYMFWWNSAZAFM-UHFFFAOYSA-N [4-methylsulfonyl-2-(trifluoromethyl)phenyl]methanamine Chemical compound CS(=O)(=O)C1=CC=C(CN)C(C(F)(F)F)=C1 JDYMFWWNSAZAFM-UHFFFAOYSA-N 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000006227 byproduct Substances 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 6
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 abstract description 4
- 230000001681 protective effect Effects 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 150000002168 ethanoic acid esters Chemical class 0.000 description 4
- 150000002311 glutaric acids Chemical class 0.000 description 4
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001470 diamides Chemical class 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- RBCARPJOEUEZLS-UHFFFAOYSA-N 3-bromopyridin-2-amine Chemical compound NC1=NC=CC=C1Br RBCARPJOEUEZLS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- XTDYIOOONNVFMA-UHFFFAOYSA-N dimethyl pentanedioate Chemical compound COC(=O)CCCC(=O)OC XTDYIOOONNVFMA-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000011218 segmentation Effects 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- FLUUWBSOLRFAKL-UHFFFAOYSA-N 1-methylsulfonyl-3-(trifluoromethyl)benzene Chemical compound CS(=O)(=O)C1=CC=CC(C(F)(F)F)=C1 FLUUWBSOLRFAKL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- TVCXVUHHCUYLGX-UHFFFAOYSA-N 2-Methylpyrrole Chemical class CC1=CC=CN1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 description 1
- PHMRPWPDDRGGGF-UHFFFAOYSA-N 2-bromoprop-1-ene Chemical class CC(Br)=C PHMRPWPDDRGGGF-UHFFFAOYSA-N 0.000 description 1
- VGSWZZTWVGLLAK-UHFFFAOYSA-N 3-oxo-3-(2-oxopropoxy)propanoic acid Chemical compound CC(=O)COC(=O)CC(O)=O VGSWZZTWVGLLAK-UHFFFAOYSA-N 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- OUWSNHWQZPEFEX-UHFFFAOYSA-N diethyl glutarate Chemical compound CCOC(=O)CCCC(=O)OCC OUWSNHWQZPEFEX-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229940058352 levulinate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- PZXIEBDIPWIRGB-UHFFFAOYSA-N methyl 2-pyridin-3-ylacetate Chemical class COC(=O)CC1=CC=CN=C1 PZXIEBDIPWIRGB-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- QCCWVNLOJADEAV-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrol-3-amine Chemical compound CN(C)C=1C=CNC=1 QCCWVNLOJADEAV-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- FPXVLCLVAIUGPW-UHFFFAOYSA-N pyridin-3-ylmethyl acetate Chemical compound CC(=O)OCC1=CC=CN=C1 FPXVLCLVAIUGPW-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000037851 severe atopic dermatitis Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention provides a kind of simple and convenient process for preparing of prostaglandin D 2 receptor inhibitor compound.With 4- mesyl -2- trifluoromethyl benzylamine (II) and 3- acetyl group glutaric acid diester (III) for raw material; it is condensed, is cyclized; then addition reaction occurs with 2- propylene halide aldehyde, pyridine cyclization occurs with ammonia, is most acidified through hydrolysis, hydrochloric acid afterwards to obtain the final product.The method of the present invention is easy to operate, and reaction condition is mild, and the three wastes are few, environmentally protective；Raw material is cheap and easy to get, at low cost；Reaction selectivity is high, and by-product is few, and purifying is simple, yield and purity is high, conducive to the industrialized production of prostaglandin D 2 receptor inhibitor compound Fevipiprant.
Description
Technical field
The present invention relates to the simple and convenient process for preparing of prostaglandin D 2 receptor inhibitor compound Fevipiprant a kind of, belong to
In technical field of medical chemistry.
Background technique
Fevipiprant (I), No. CAS is [872365-14-5], and chemical name is [1- (4- mesyl -2- fluoroform
Base phenyl) methyl -2- methyl-1 H- pyrrolo- [2,3-b] pyridin-3-yl] acetic acid is a kind of forefront developed by Novartis Co., Ltd
Parathyrine D2 receptor (DP2/CRTh2) inhibitor is mainly used for treating asthma.Prove that the candidate molecules have according to I test of clinic
More outstanding safety and tolerance, great clinical development potentiality value carry out III phase clinic in the U.S. at present, are a kind of non-
Often there is the treatment of market prospects slightly to moderate persistent asthma, moderate to severe atopic dermatitis and allergic rhinitis candidate's medicine
Object.
The chemical structural formula of Fevipiprant is as follows:
About the report of Fevipiprant synthetic method in currently available technology.
Such as, patent document WO2005123731 is using 4- mesyl -2- trifluoromethylated benzaldehyde as raw material, by reduction,
Bromo obtains 4- mesyl -2- trifluoromethyl bromobenzyl, then with 2- methyl-1 H- pyrroles [2,3-b] and pyridin-3-yl-acetic acid
Methyl esters condensation, hydrolysis, acidification obtain target compound, and corresponding synthetic route is referring to synthetic route 1.
But in said synthesis route 1,2- methyl-1 H- pyrroles [2,3-b] and pyridin-3-yl-methyl acetate price compared with
Height is not easy to obtain；Reaction selectivity is low, needs cumbersome purifying；Being total to there are pyridine ring and pyrrole ring in condensation step simultaneously
Yoke leads to the generation of pyridine ring alkylate by-product, which is higher than 40%, needs cumbersome separation, total recovery is most
Height is only 50% or so, and quantity of three wastes is big, is unfavorable for the industrialized production of Fevipiprant.
For another example, Chinese patent literature CN106188040A is using 2- amino -3- bromopyridine as raw material, first and 4- mesyl -
2- trifluoromethylated benzaldehyde is condensed to form Schiff base intermediate, then prepares the bromo- N- of 3- (4- (methylsulfonyl through sodium borohydride reduction
Base) -2- (trifluoromethyl) phenyl) methvl-pyridinium -2- amine, then with 3- levulinate or 3- acetonyl malonate into
Row Liv Ullmann ring closure reaction, then Fevipiprant, total recovery 57.0-73.7% are prepared by hydrolysis, acidification or hydrolysis-decarboxylation,
Corresponding synthetic route is referring to synthetic route 2.
But the raw materials used 2- amino -3- bromopyridine price of the route is high, is not easy to obtain；The catalysis used of Liv Ullmann ring closure reaction
Agent and co-catalysis dosage are big, and reaction temperature is high, the time is long (120 DEG C, 12 hours), high operation requirements；Products obtained therefrom color weight, gold
Category residual quantity is big, and yield section is big, and quantity of three wastes is big, is unfavorable for green industrialized production.
Therefore the green industrialized production line for establishing easy to operate, at low cost, reaction selectivity and high income, for
The III phase clinical research of Fevipiprant and after market are of great significance.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of prostaglandin D 2 receptor inhibitor compound
The simple and convenient process for preparing of Fevipiprant.This method is easy to operate, and reaction condition is mild, and the three wastes are few, environmentally protective；Raw material is honest and clean
Valence is easy to get, at low cost；Reaction selectivity is high, and by-product is few, and purifying is simple, yield and purity is high, conducive to the work of Fevipiprant
Industry metaplasia produces.
Term explanation:
II compound of formula: 4- mesyl -2- trifluoromethyl benzylamine (II)；
III compound of formula: 3- acetyl group glutaric acid diester (III)；
IV compound of formula: N- (4- mesyl -2- trifluoromethyl) methyl -2- methyl -4,5- pyrrolin -5-
Ketone -3- acetic acid esters (IV)；
V compound of formula: N- (4- mesyl -2- trifluoromethyl) methyl -2- methyl -4- (halogenated -2- formyl of 2-
Base) ethyl -4,5- pyrrolin -5- ketone -3- acetic acid esters (V)；
VI compound of formula: [1- (4- mesyl -2- trifluoromethyl) methyl -2- methyl-1 H- pyrrolo- [2,3-b]
Pyridin-3-yl] acetic acid esters (VI)；
Type I compound: Fevipiprant (I).
In this specification, compound number is completely the same with formula numbers, reference relationship having the same, with compound
Structural formula is foundation.
Technical scheme is as follows:
The preparation method of prostaglandin D 2 receptor inhibitor compound Fevipiprant shown in formula I a kind of, including step
It is rapid:
(1) in solvent, under the action of acid catalyst, II compound of formula and III compound of formula are through condensation, cyclization
Obtain IV compound of formula；
Wherein, formula III, in IV structural formula of compound, R is-CH3、-C2H5、-C3H7Or-C4H9；
(2) under the action of base catalyst, IV compound of formula and 2- propylene halide aldehyde are through V chemical combination of addition reaction preparation formula
Object；In the presence of ammonia, V compound of formula is cyclized to obtain VI compound of formula through pyridine；Then it is acidified to obtain through hydrolysis, hydrochloric acid
Fevipiprant(Ⅰ)；
Wherein, in V structural formula of compound of formula, X is Cl or Br；In formula V, IV structural formula of compound, the meaning and formula III of R
The meaning of R is identical in structural formula of compound.
, according to the invention it is preferred to, solvent energy azeotrope with water described in step (1), and make 50-100 DEG C of azeotropic point；It is excellent
Choosing, the solvent be ethyl alcohol, 1- propyl alcohol, 2- propyl alcohol, n-butyl alcohol, 2- butanol, isobutanol, the tert-butyl alcohol, 1,2- dichloroethanes, 1,
The combination of one or more of 2- dichloropropane, toluene, hexamethylene, acetonitrile or tetrahydrofuran；The solvent and formula II
The mass ratio of compound is (5-30): 1；Preferably, the mass ratio of II compound of the solvent and formula is (7-14): 1.
, according to the invention it is preferred to, acid catalyst described in step (1) is Bronsted acid or Lewis acid, preferably to methyl
The combination of one or more of benzene sulfonic acid, benzene sulfonic acid, the 98wt% concentrated sulfuric acid, zinc chloride, stannous chloride or alchlor；
The quality of the acid catalyst is the 0.5%-5.0% of II compound quality of formula；Preferably, the quality of the acid catalyst is formula
The 1.0%-3.0% of II compound quality.
, according to the invention it is preferred to, the molar ratio of II compound of formula III compound described in step (1) and formula is (0.9-
1.5):1。
, according to the invention it is preferred to, setting-up point described in step (1) is 30-50 DEG C, and cyclization temperature is
60-100℃.Condensation reaction time is 2-4 hours, and the cyclization time is 2-5 hours.
, according to the invention it is preferred to, base catalyst described in step (2) is piperidines, nafoxidine, morpholine, 1,8- phenodiazine
Miscellaneous bicyclic [5.4.0] 11 carbon -7- alkene (DBU), 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 4- dimethylamino pyrrole
The combination of one or more of pyridine, potassium tert-butoxide, sodium ethoxide or sodium methoxide；The quality of the base catalyst is that formula II is changed
Close the 1.0%-5.0% of amount of substance；Preferably, the quality of the base catalyst is the 3.0%-5.0% of II compound quality of formula.
, according to the invention it is preferred to, 2- propylene halide aldehyde described in step (2) is 2- chloroacrolein or 2- bromopropene aldehyde；
The molar ratio of II compound of 2- propylene halide aldehyde described in step (2) and formula is (1.0-1.5): 1.
, according to the invention it is preferred to, addition reaction temperature described in step (2) is 0-100 DEG C；Preferably, in step (2)
The addition reaction temperature is 30-50 DEG C.The addition reaction time is 2-10 hours；Preferably, the addition reaction time is that 3-5 is small
When.
, according to the invention it is preferred to, ammonia described in step (2) is molten using ammonia, ammonium hydroxide, methanolic ammonia solution or cholamine
Liquid；The molar ratio of II compound of the ammonia and formula is (3.0-5.0): 1.
, according to the invention it is preferred to, it is 30-100 DEG C that pyridine described in step (2), which is cyclized reaction temperature,；Preferably, described
It is 50-70 DEG C that pyridine, which is cyclized reaction temperature,.The pyridine cyclisation reaction time is 2-8 hours；Preferably, the pyridine cyclisation reaction time is
3-5 hours.
, according to the invention it is preferred to, hydrolysis described in step (2) is carried out in the presence of alkali, and the alkali is using matter
Measure sodium hydrate aqueous solution, potassium hydroxide aqueous solution or the lithium hydroxide aqueous solution that concentration is 10%-50%；The alkali and formula II
The molar ratio of compound is (1.0-2.0): 1.
, according to the invention it is preferred to, hydrolysising reacting temperature described in step (2) is 0-100 DEG C；Preferably, the hydrolysis
Reaction temperature is 20-40 DEG C.Hydrolysis time is 1-5 hours；Preferably, hydrolysis time is 2-3 hours.
, according to the invention it is preferred to, in step (2), the reaction liquid layer that will be obtained after hydrolysis, to the water separated
Active carbon is added in layer, 20-30 DEG C of stirring is decolourized 0.5-2 hours, then filtering carries out hydrochloric acid acidification.
, according to the invention it is preferred to, the acidification of hydrochloric acid described in step (2) is the hydrochloric acid for the use of mass concentration being 20-35%
The pH value for being acidified to system is 2.0-2.5.
, according to the invention it is preferred to, the reaction in reaction and step (2) in step (1) is " one kettle way " progress, step
(1) product obtained without isolation, directly carries out the reaction of step (2).
Preparation step of the invention is described as following synthetic route 3:
Wherein, in III, IV, V, VI structural formula of compound of formula, R is-CH3、-C2H5、-C3H7Or-C4H9；V compound of formula
In structural formula, X is Cl or Br.
Technical characterstic of the invention and the utility model has the advantages that
1, the present invention provides a kind of new Fevipiprant preparation method, utilizes 4- mesyl -2- trifluoromethyl benzylamine
(II) and 3- acetyl group glutaric acid diester (III) is raw material, obtains N- (4- mesyl -2- fluoroform through condensation-cyclization
Base phenyl) methyl -2- methyl -4,5- pyrrolin -5- ketone -3- acetic acid esters (IV), it is then anti-through addition with 2- propylene halide aldehyde
N- (4- mesyl -2- trifluoromethyl) methyl -2- methyl -4- (halogenated -2- formoxyl of 2-) ethyl -4,5- two should be prepared
Hydrogen pyrroles's -5- ketone -3- acetic acid esters (V), then [1- (4- mesyl -2- trifluoromethylbenzene is obtained through pyridine cyclization with ammonia
Base) methyl -2- methyl-1 H- pyrrolo- [2,3-b] pyridin-3-yl] acetic acid esters (VI), hydrolyzed under basic conditions, hydrochloric acid are acidified
To Fevipiprant (I).
2, raw material of the present invention is cheap and easy to get, and process flow is brief, can prepare Fevipiprant (I) through " one kettle way ", instead
Mild condition is answered, it is easy to operate, it is easy to accomplish, at low cost；Preparation process three wastes yield is few, and technique is environmentally protective；The present invention
Method reaction selectivity is high, and by-product is few, and purifying is simple, yield and purity is high (total recovery is up to 88.6%), and is not related to
The problem of metal residual, conducive to the industrialized production of Fevipiprant.
3, reaction selectivity involved by route of the present invention is high, carries out reducing two points by condensation-cyclization temperature programming
It is secondary anti-that sub- 4- mesyl -2- trifluoromethyl benzylamine (II) and a molecule 3- acetyl group glutaric acid diester (III) carry out diamidesization
Probability is answered, addition is carried out using the higher activity of the amide ortho position methylene of IV compound of formula and 2- propylene halide aldehyde, establishes
Entirely route reaction is highly selective, and products obtained therefrom color is good, yield and purity is high.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
Embodiment is raw materials used and reagent is commercial product." % " in embodiment is mass percent, is illustrated
Except.
Yield in embodiment is molar yield.
The preparation of embodiment 1:Fevipiprant (I)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, water segregator and reflux condensing tube, 200 grams of first are added
Benzene, 25.3 grams of (0.1 mole) 4- mesyl -2- trifluoromethyl benzylamines (II), 21.0 grams of (0.1 mole) 3- acetyl group glutaric acids
Dimethyl ester (III1), 0.5 gram of p-methyl benzenesulfonic acid, 45 to 50 DEG C are stirred to react 2 hours, and 82 to 85 DEG C are stirred to react 4 hours, together
When separate the water that azeotropic separates.20 to 25 DEG C are cooled to, is added 1.0 grams of DBU, 10.0 grams of (0.11 mole) 2- chloroacroleins, 40
It is stirred to react 4 hours to 45 DEG C.40.0 grams of (0.4 mole) 17wt% methanolic ammonia solutions are added, 50 to 55 DEG C to be stirred to react 4 small
When.20 to 25 DEG C are cooled to, is added 250 grams of water, the sodium hydrate aqueous solution of 30 grams of 20wt%, 25 to 30 DEG C to be stirred to react 2 small
When, 0.5 gram of active carbon is added into the water layer separated for layering, and 25 to 30 DEG C of stirrings are decolourized 1 hour, and filtering, filtrate uses 35wt%
Hydrochloric acid acidification is filtered until system pH 2.0-2.5, dry, obtains 37.5 grams of white solid Fevipiprant (I), yield is
87.9%, liquid phase purity 99.9%.
The nuclear magnetic data of products therefrom is as follows:
1H NMR(400MHz,DMSO-d6):
2.26 (3H, s), 3.26 (3H, s), 3.66 (2H, s), 5.71 (2H, s), 6.46 (1H, d J=8.3), 7.07
(1H, dd J=7.7,4.8), 7.96 (1H, d, J=7.8), 8.01 (1H, d, J=8.3), 8.11 (1H, d, J=4.7), 8.22
(1H,s),12.28(1H,brs).
The preparation of embodiment 2:Fevipiprant (I)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, water segregator and reflux condensing tube, it is added 200 gram 1,2-
Dichloroethanes, 25.3 grams of (0.1 mole) 4- mesyl -2- trifluoromethyl benzylamines (II), 23.0 grams of (0.1 mole) 3- acetyl group
Ethyl glutarate (III2), 0.5 gram of 98wt% concentrated sulfuric acid, 45 to 50 DEG C are stirred to react 2 hours, and 70 to 75 DEG C are stirred to react 5
Hour, while separating the water that azeotropic separates.20 to 25 DEG C are cooled to, 1.2 grams of DBU, 13.5 grams of (0.1 mole) 2- bromopropenes are added
Aldehyde, 35 to 40 DEG C are stirred to react 4 hours.40.0 grams of (0.4 mole) 17wt% methanolic ammonia solutions are added, 50 to 55 DEG C are stirred to react
4 hours.20 to 25 DEG C are cooled to, 250 grams of water are added, the sodium hydrate aqueous solution of 30 grams of 20wt%, 20 to 25 DEG C are stirred to react 2
Hour, 0.5 gram of active carbon is added into the water layer separated for layering, and 25 to 30 DEG C of stirrings are decolourized 1 hour, and filtering, filtrate is used
The acidification of 35wt% hydrochloric acid is filtered until system pH 2.0-2.5, dry, obtains 37.3 grams of white solid Fevipiprant (I),
Yield is 87.5%, liquid phase purity 99.8%.
The preparation of embodiment 3:Fevipiprant (I)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, water segregator and reflux condensing tube, 200 grams of first are added
Benzene, 25.3 grams of (0.1 mole) 4- mesyl -2- trifluoromethyl benzylamines (II), 21.0 grams of (0.1 mole) 3- acetyl group glutaric acids
Dimethyl ester (III1), 0.5 gram of p-methyl benzenesulfonic acid, 40 to 45 DEG C are stirred to react 3 hours, and 82 to 85 DEG C are stirred to react 4 hours, together
When separate the water that azeotropic separates.Be cooled to 20 to 25 DEG C, be added 1.2 grams of DBU, 13.5 grams of (0.1 mole) 2- bromopropene aldehyde, 40 to
45 DEG C are stirred to react 4 hours.40.0 grams of (0.4 mole) 17wt% methanolic ammonia solutions are added, 50 to 55 DEG C are stirred to react 4 hours.
20 to 25 DEG C are cooled to, 250 grams of water are added, the potassium hydroxide aqueous solution of 35 grams of 20wt%, 20 to 25 DEG C are stirred to react 2 hours,
0.5 gram of active carbon is added into the water layer separated for layering, and 25 to 30 DEG C of stirrings are decolourized 1 hour, filtering, filtrate 35wt% salt
Acid acidification is filtered until system pH 2.0-2.5, dry, obtains 37.8 grams of white solid Fevipiprant (I), yield is
88.6%, liquid phase purity 99.9%.
The preparation of embodiment 4:Fevipiprant (I)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, water segregator and reflux condensing tube, 250 grams of 2- fourths are added
Alcohol, 25.3 grams of (0.1 mole) 4- mesyl -2- trifluoromethyl benzylamines (II), 21.0 grams of (0.1 mole) 3- acetyl group glutaric acids
Dimethyl ester (III1), 0.5 gram of zinc chloride, 45 to 50 DEG C are stirred to react 2 hours, and 85 to 100 DEG C are stirred to react 4 hours, the same to time-division
The water that azeotropic separates out.20 to 25 DEG C are cooled to, is added 1.2 grams of DBU, 13.5 grams of (0.1 mole) 2- bromopropene aldehyde, 40 to 45 DEG C
It is stirred to react 4 hours.40.0 grams of (0.4 mole) 17wt% ammonia spirits are added, 50 to 55 DEG C are stirred to react 4 hours.It is cooled to
20 to 25 DEG C, 250 grams of water are added, the sodium hydrate aqueous solution of 30 grams of 20wt%, 25 to 30 DEG C are stirred to react 2 hours, layering, to
0.5 gram of active carbon is added in the water layer separated, 25 to 30 DEG C of stirrings are decolourized 1 hour, and filtering, filtrate is acidified straight with 35wt% hydrochloric acid
To system pH 2.0-2.5, filter, it is dry, obtain 36.3 grams of white solid Fevipiprant (I), yield 85.1%, liquid
Phase purity 99.6%.
Comparative example: the preparation of Fevipiprant (I)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, water segregator and reflux condensing tube, 200 grams of first are added
Benzene, 25.3 grams of (0.1 mole) 4- mesyl -2- trifluoromethyl benzylamines (II), 21.0 grams of (0.1 mole) 3- acetyl group glutaric acids
Dimethyl ester (III1), 0.5 gram of p-methyl benzenesulfonic acid, 82 to 85 DEG C are stirred to react 4 hours, while separating the water that azeotropic separates.It is cold
But to 20 to 25 DEG C, 1.0 grams of DBU are added, 10.0 grams of (0.11 mole) 2- chloroacroleins, 40 to 45 DEG C are stirred to react 4 hours.Add
Enter 40.0 grams of (0.4 mole) 17wt% methanolic ammonia solutions, 50 to 55 DEG C are stirred to react 4 hours.20 to 25 DEG C are cooled to, is added
250 grams of water, the sodium hydrate aqueous solution of 30 grams of 20wt%, 25 to 30 DEG C are stirred to react 2 hours, layering, into the water layer separated
0.5 gram of active carbon is added, 25 to 30 DEG C of stirrings are decolourized 1 hour, and filtering, filtrate is acidified with 35wt% hydrochloric acid until system pH
2.0-2.5 is filtered, dry, obtains 29.3 grams of white solid Fevipiprant (I), yield 68.7%, liquid phase purity
99.5%.
Compared from above embodiments and this comparative example: condensation, the temperature programming of cyclization, segmentation are carried out for anti-
Yield is answered to be affected.Analysis reason is temperature programming, segmentation carries out being conducive to 4- mesyl -2- trifluoromethyl benzylamine and 3-
The carbonyl of acetyl group dimethyl glutarate is reacted, and then reduces two molecule 4- mesyl -2- trifluoromethyl benzylamines and one
Molecule 3- acetyl group dimethyl glutarate carries out diamides side reaction, although the by-product generated can pass through hydrolysis
(in not reacting at use temperature, diamides by-product is dissolved in organic solvent, does not dissolve in for diamides by-product and alkali for removing
Water can remove when layering), target product purity is had substantially no effect on, but be detrimental to improve target product yield.
Claims (10)
1. a kind of preparation method of prostaglandin D 2 receptor inhibitor compound shown in formula I, comprising steps of
(1) in solvent, under the action of acid catalyst, II compound of formula and III compound of formula obtain formula through condensation, cyclization
IV compound；
Wherein, formula III, in IV structural formula of compound, R is-CH3、-C2H5、-C3H7Or-C4H9；
(2) under the action of base catalyst, IV compound of formula and 2- propylene halide aldehyde are through V compound of addition reaction preparation formula；In
In the presence of ammonia, V compound of formula is cyclized to obtain VI compound of formula through pyridine；Then it is acidified to obtain through hydrolysis, hydrochloric acid
Fevipiprant(Ⅰ)；
Wherein, in V structural formula of compound of formula, X is Cl or Br；In formula V, IV structural formula of compound, the meaning and III chemical combination of formula of R
The meaning of R is identical in object structural formula.
2. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(1) in, including one or more in the following conditions:
(a) the solvent energy azeotrope with water, and make 50-100 DEG C of azeotropic point；Preferably, the solvent be ethyl alcohol, 1- propyl alcohol,
2- propyl alcohol, n-butyl alcohol, 2- butanol, isobutanol, the tert-butyl alcohol, 1,2- dichloroethanes, 1,2- dichloropropane, toluene, hexamethylene, acetonitrile
Or the combination of one or more of tetrahydrofuran；The mass ratio of II compound of the solvent and formula is (5-30): 1；It is excellent
Choosing, the mass ratio of II compound of the solvent and formula is (7-14): 1；
(b) acid catalyst be Bronsted acid or Lewis acid, preferably p-methyl benzenesulfonic acid, benzene sulfonic acid, the 98wt% concentrated sulfuric acid,
The combination of one or more of zinc chloride, stannous chloride or alchlor；The quality of the acid catalyst is that formula II is changed
Close the 0.5%-5.0% of amount of substance；Preferably, the quality of the acid catalyst is the 1.0%-3.0% of II compound quality of formula；
(c) molar ratio of II compound of the formula III compound and formula is (0.9-1.5): 1.
3. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(1) setting-up point described in is 30-50 DEG C, and cyclization temperature is 60-100 DEG C.
4. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(2) in, including one or more in the following conditions:
(a) base catalyst is piperidines, nafoxidine, morpholine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0]
(DBU), 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 4-dimethylaminopyridine, potassium tert-butoxide, sodium ethoxide or methanol
The combination of one or more of sodium；The quality of the base catalyst is the 1.0%-5.0% of II compound quality of formula；It is excellent
Choosing, the quality of the base catalyst is the 3.0%-5.0% of II compound quality of formula；
(b) the 2- propylene halide aldehyde is 2- chloroacrolein or 2- bromopropene aldehyde；2- propylene halide aldehyde and formula described in step (2)
The molar ratio of II compound is (1.0-1.5): 1.
5. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(2) addition reaction temperature described in is 0-100 DEG C；Preferably, addition reaction temperature described in step (2) is 30-50 DEG C.
6. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(2) ammonia described in is using ammonia, ammonium hydroxide, methanolic ammonia solution or cholamine solution；The molar ratio of II compound of the ammonia and formula
For (3.0-5.0): 1.
7. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(2) it is 30-100 DEG C that pyridine described in, which is cyclized reaction temperature,；Preferably, the pyridine cyclisation reaction temperature is 50-70 DEG C.
8. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(2) in, including one or more in the following conditions:
(a) hydrolysis is carried out in the presence of alkali, and the alkali is the sodium hydroxide water for the use of mass concentration being 10%-50%
Solution, potassium hydroxide aqueous solution or lithium hydroxide aqueous solution；The molar ratio of II compound of the alkali and formula is (1.0-2.0): 1；
(b) hydrolysising reacting temperature is 0-100 DEG C；Preferably, the hydrolysising reacting temperature is 20-40 DEG C；
(c) reaction liquid layer that will be obtained after hydrolysis, active carbon is added into the water layer separated, and 20-30 DEG C of stirring is de-
Color 0.5-2 hours, then filtering carries out hydrochloric acid acidification.
9. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
(2) it is 2.0-2.5 that the acidification of hydrochloric acid described in, which is the pH value that the hydrochloric acid for the use of mass concentration being 20-35% is acidified to system,.
10. the preparation method of prostaglandin D 2 receptor inhibitor compound according to claim 1, which is characterized in that step
Suddenly the reaction in the reaction in (1) and step (2) for " one kettle way " progress, the product that step (1) obtains without isolation, directly into
The reaction of row step (2).
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123731A2 (en) * | 2004-06-17 | 2005-12-29 | Novartis Ag | Pyrrolopyridine derivatives and their use as crth2 antagonists |
| CN106188040A (en) * | 2016-06-28 | 2016-12-07 | 浙江宏鑫染化材料有限公司 | A kind of Fevipiprant and the preparation method of intermediate thereof |
| WO2017056001A1 (en) * | 2015-09-29 | 2017-04-06 | Novartis Ag | Process for preparing 1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1h-pyrrolo [2,3-b]pyridin-3-yl-acetic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123731A2 (en) * | 2004-06-17 | 2005-12-29 | Novartis Ag | Pyrrolopyridine derivatives and their use as crth2 antagonists |
| WO2017056001A1 (en) * | 2015-09-29 | 2017-04-06 | Novartis Ag | Process for preparing 1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1h-pyrrolo [2,3-b]pyridin-3-yl-acetic acid |
| CN106188040A (en) * | 2016-06-28 | 2016-12-07 | 浙江宏鑫染化材料有限公司 | A kind of Fevipiprant and the preparation method of intermediate thereof |
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Denomination of invention: A Simple Preparation Method of Prostaglandin D2 Receptor Inhibitor Effective date of registration: 20221213 Granted publication date: 20200925 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |