CN110183367A - A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization - Google Patents
A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization Download PDFInfo
- Publication number
- CN110183367A CN110183367A CN201910498948.7A CN201910498948A CN110183367A CN 110183367 A CN110183367 A CN 110183367A CN 201910498948 A CN201910498948 A CN 201910498948A CN 110183367 A CN110183367 A CN 110183367A
- Authority
- CN
- China
- Prior art keywords
- acid
- ethyl
- compound
- benzyloxycarbonyl group
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 239000002904 solvent Substances 0.000 claims abstract description 33
- 239000002253 acid Substances 0.000 claims abstract description 24
- 150000002148 esters Chemical class 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 7
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims abstract description 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims abstract description 5
- LORZIARWNGRWJL-UHFFFAOYSA-N n-methoxy-1-phenyl-n-(trimethylsilylmethyl)methanamine Chemical compound C[Si](C)(C)CN(OC)CC1=CC=CC=C1 LORZIARWNGRWJL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- 238000007171 acid catalysis Methods 0.000 claims abstract description 4
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 12
- 229940126062 Compound A Drugs 0.000 claims description 12
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 12
- 239000000543 intermediate Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000012545 processing Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 3
- -1 trimethylsilylmethyl Chemical group 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000007859 condensation product Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 16
- 230000008569 process Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000012805 post-processing Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- WYQFJHHDOKWSHR-MNOVXSKESA-N (3S,4R)-3-ethyl-4-(1,5,7,10-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),3,7,9,11-pentaen-12-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide Chemical compound CC[C@@H]1CN(C(=O)NCC(F)(F)F)C[C@@H]1C1=CN=C2N1C(C=CN1)=C1N=C2 WYQFJHHDOKWSHR-MNOVXSKESA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 2
- 102000042838 JAK family Human genes 0.000 description 2
- 108091082332 JAK family Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 229950000088 upadacitinib Drugs 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 102000015617 Janus Kinases Human genes 0.000 description 1
- 108010024121 Janus Kinases Proteins 0.000 description 1
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical class CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a kind of (3R suitable for industrialization, 4S) the synthetic method of -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, it include: to prepare intermediate condensation product through being condensed ring closure reaction under acid catalysis in a solvent using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material；After ethyl chloroformate is added in intermediate; reaction obtains another intermediate; continue and benzyl chloroformate through acylation reaction prepares N protection midbody products; after ester hydrolysis reaction; with hydrogen through asymmetric reduction reaction; obtain (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid.The present invention is reacted by five steps, purity and all higher (3R of yield are obtained, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid solves the problems, such as that quality in the prior art and yield are difficult to control, and sufficient raw material midbody is provided for Buddhist nun to synthesize black pa.
Description
Technical field
The present invention relates to a kind of conjunctions of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization
At method, belong to chipal compounds synthesis technical field.
Background technique
JAK inhibitor alternative inhibits JAK kinases, blocks JAK/STAT access.JAK-STAT signal path is
The signal transduction pathway that one of discovered in recent years is stimulated by cell factor participates in the proliferation of cell, differentiation, apoptosis and immune
Many important biological processes such as adjusting.JAK is the target spot that industry is expected extensively.The support method of current existing Pfizer is replaced
Buddhist nun is granted for treating rheumatoid arthritis, and sales volume reached 9.27 hundred million dollars in 2016.Novartis/Incyte
Ruxolitinib(Luso replaces Buddhist nun) it is granted for treating myelofibrosis, polycythemia vera, global marketing volume in 2016
Also 14.34 hundred million dollars have been reached.
The new drug crow pa of AbbVie company is a kind of new oral selection for Buddhist nun (upadacitinib, code name ABT-494)
Property JAK-1 inhibitor, treatment rheumatoid arthritis, psoriatic arthritis the III phase study it is in progress.In addition,
Upadacitinib is also exploited for treatment Crohn disease, ulcerative enteritis and mandatory rachitis.On September 7th, 2017,
AbbVie announces upadacitinib (ABT-494) treatment the random of atopic dermatitis, placebo, dosage range
IIb research is reached home, and black pa shows fabulous effect for each dosage group clinical trial of Buddhist nun as the result is shown, which will be to crow
Pa pushes further clinical trial to for Buddhist nun or great positive effect is played in listing., it is expected that black pa will have for Buddhist nun it is wide
Market value, black pa will also have wide industrial value for Buddhist nun's bulk pharmaceutical chemicals.
Black pa is the hand-type heterocyclic compound containing two chiral centres for Buddhist nun's bulk pharmaceutical chemicals, and synthesis difficulty is very big.The website MCD is aobvious
Show that maximum 25mg specification crow pa reaches 1620 U.S. dollars for Buddhist nun's compound price.Document report crow pa is economic cooperation for the synthetic route of Buddhist nun
It has no progeny at two pieces and is no less than the reaction synthesis of 4 steps again.Wherein, hand-type segment compound is the key that technique and its synthesis
Difficult point, integrated artistic and final products property to the compound play conclusive influence, and black pa is reported for Buddhist nun and closed
It is as follows at route:
Hand-type segment compound prior art reports that yield is lower (total recovery is less than 15%), and technique is main to hand-type Pureness control
It is repeatedly split after raceme or process route is too long, separate step severe reaction conditions, technical process by preparing
There is the unfriendly condition of environment simultaneously.How technique entirety yield is improved under conditions of guaranteeing that hand-type purity is greater than 99%, shorten work
Skill step reduces process costs, it will plays great influence to black pa for Buddhist nun's end product quality and price.
Patent CN104370909A//US2011/0311474A1//WO201106888A1 reports following route:
Using 2- alkynes ethyl valerate as starting material, alkene, then cyclization are become by hydrogenating reduction alkynes under Lindlar catalyst
Racemization type intermediate is prepared, then CBZ protecting group on debenzylation, after hydrolysis, then passes through 3 times or more fractionations acquisition hand-type
Purity is greater than 99% target product (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid.The major defect of the technique is
Synthesising racemation type precursor, then splits again, theoretical highest yield 50%, and net yield is about that 14.75%(is respectively walked open receipts by document
Rate data combination resolution yield 100% calculates).Meanwhile product boiling point is extremely low after the reduction of the technique first step, subtracts at 25 DEG C of temperature
Pressure is i.e. readily volatilized, largely effects on process recovery ratio, is unfavorable for industrialization production, while intermediate is ultraviolet after third step deprotection
Absorption is weaker, is unfavorable for technical process HPLC tracking.
Patent WO2017066775A1 reports following synthetic route:
Report prepares final product using glycine ethyl ester derivative and ethyl acrylate as starting material, through the reaction of 6 steps.It should
Process route major advantage is starting material economy, while synthesizing target product using asymmetric reduction, and single step hand-type yield has
It significantly improves.Main shortcoming is that technique overall step is more, while separate step needs to control the reaction of anhydrous or anaerobic,
The protecting group or catalyst used simultaneously is not easy removal in process influences Quality control of intermediates.The first step is reacted in industrialization
It operates more demanding in amplification, is unfavorable for industrialization.
In conclusion avoiding above series of problem, (3R, 4S) -1- benzyloxycarbonyl group -4- second of suitable industrialization is developed
Base pyrroles's -3- carboxylic acid synthesis technology is very necessary.
Summary of the invention
The technical problem to be solved by the present invention is to overcome prior art production technology complexity, defect rambunctious, provide
A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid of suitable industrialization.
Above-mentioned technical purpose of the invention has the technical scheme that
A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization, feature
It is, comprising the following steps:
S1, using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material, in a solvent
Intermediate condensation midbody product compound A, the structural formula of the compound A are prepared through being condensed ring closure reaction under acid catalysis
Are as follows:
；
Compound A is added in solvent by S2, stirring, and after 0 ~ 5 DEG C of addition ethyl chloroformate, 1 ~ 2h is reacted at 20 ~ 25 DEG C
Afterwards, alcohols solvent is added, the reaction was continued at 40 ~ 90 DEG C, obtains midbody product compound B, the structural formula of the compound B
Are as follows:
；
S3, under the conditions of alkali, compound B prepares N protection intermediates through acylation reaction with benzyl chloroformate in a solvent and produces
Compounds C, the structural formula of the compound C are as follows:
；
S4, under alkaline condition, compound C prepares midbody product compound D, describedization through ester hydrolysis reaction in a solvent
Close the structural formula of object D are as follows:
；
Compound D is crystallized to obtain intermediate sterling through processing by S5, in a solvent, under the conditions of catalyst is existing, is passed through with hydrogen
Asymmetric reduction reaction obtains (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
The synthetic route of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid are as follows:
By using above-mentioned technical proposal, five steps react (3R, the 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic being prepared
Acid, and easily-controlled reaction conditions.
Preferably, the valerylene acid esters in the S1 is valerylene acid methyl esters, valerylene acetoacetic ester or the tertiary fourth of valerylene acid
One of ester；The R1For methyl, ethyl or tert-butyl；Solvent in the S1 be ethyl acetate, acetonitrile, toluene, acetone,
Any one of methylene chloride, chloroform, 1,2- dichloroethanes or a combination thereof；Acid in the S1 is acetic acid, methyl sulphur
Any one of acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid or a combination thereof.
Preferably, valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine equivalent in the S1
Ratio is 0.8:1 ~ 1:2.
Preferably, the reaction temperature in the S1 is -5 ~ 50 DEG C.
Preferably, solvent is ethyl acetate, acetonitrile, toluene, acetone, methylene chloride, chloroform, 1,2- bis- in the S2
Any one of chloroethanes or a combination thereof；The equivalents ratio of compound A and ethyl chloroformate is (0.8 ~ 1) in the S2:
(1 ~ 5)；Alcohols solvent is one of methanol, ethyl alcohol, isopropanol or combinations thereof in the S2.
Preferably, the solvent in the S3 is any in ethyl acetate, acetonitrile, toluene, acetone, methylene chloride and water
Kind or a combination thereof；Alkali in the S3 is triethylamine, DBU, sodium carbonate, potassium carbonate, potassium hydroxide, any in saleratus
Kind or combinations thereof；
The equivalents ratio that feeds intake of the compound B and benzyl chloroformate is (0.8 ~ 1): (1 ~ 5).
Preferably, the solvent in the S4 is in acetonitrile, toluene, acetone, methylene chloride, 1,2- dioxane and water
It is any or a combination thereof；Alkali in the S4 is potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, DBU, hydroxide
Potassium, lithium hydroxide, sodium methoxide, in sodium ethoxide any one or combinations thereof；The throwing amount equivalents ratio of the compound C and alkali is
(0.8 ~ 1): (1 ~ 5).
Preferably, the solvent in the S5 is toluene, acetone, methylene chloride, 1,2- dioxane, methanol, ethyl alcohol, isopropyl
Any one of alcohol, benzyl alcohol and water or a combination thereof；Alkali in the S5 is triethylamine, diisopropyl ethyl amine, two different
Propylamine, DBU, potassium hydroxide, in lithium hydroxide any one or combinations thereof；The throwing amount of compound D and alkali in the S5 are worked as
Amount ratio is 1:(1 ~ 10).
Preferably, the throwing amount equivalents ratio of the compound D and catalyst is 1:(0.001 ~ 0.3).
Preferably, the catalyst is S-segphos Ru (OAc) 2.
By using above-mentioned technical proposal, so that reaction rate improves, (3R, 4S) -1- benzyloxy suitable for industrialization is obtained
Carbonyl -4- N-ethyl pyrrole N -3- carboxylic acid.
In conclusion the invention has the following advantages:
(1) a kind of synthetic method of (3R, 4S) -1- substitution -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization of the invention is logical
The reaction of five steps is crossed, operating method is simple, has obtained purity and all higher (3R, the 4S) -1- benzyloxycarbonyl group -4- ethyl pyrrole of yield
- 3- carboxylic acid is coughed up, solves the problems, such as that quality in the prior art and yield are difficult to control, has saved the reaction time, reduced system
Standby cost；
(2) the synthetic method behaviour of a kind of (3R, 4S) -1- substitution -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization of the invention
It is easily controllable to make condition, is split without multiple, reduces processing step.
Specific embodiment
The invention will be further described below.Following embodiment is only used for clearly illustrating technical side of the invention
Case, and not intended to limit the protection scope of the present invention.
A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization, it is special
Sign is, comprising the following steps:
S1, using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material, in a solvent
Intermediate condensation midbody product compound A, the structural formula of the compound A are prepared through being condensed ring closure reaction under acid catalysis
Are as follows:
；
Compound A is added in solvent by S2, stirring, and after 0 ~ 5 DEG C of addition ethyl chloroformate, 1 ~ 2h is reacted at 20 ~ 25 DEG C
Afterwards, alcohols solvent is added, the reaction was continued at 40 ~ 90 DEG C, obtains midbody product compound B, the structural formula of the compound B
Are as follows:
；
S3, under the conditions of alkali, compound B prepares N protection intermediates through acylation reaction with protecting group reagent in a solvent and produces
Compounds C, the structural formula of the compound C are as follows:
；
S4, under alkaline condition, compound C prepares midbody product compound D, describedization through ester hydrolysis reaction in a solvent
Close the structural formula of object D are as follows:
；
Compound D is crystallized to obtain intermediate sterling through processing by S5, in a solvent, under the conditions of catalyst is existing, is passed through with hydrogen
Asymmetric reduction reaction obtains (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
The synthetic route of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid are as follows:
By using above-mentioned technical proposal, five steps react (3R, the 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic being prepared
Acid, and easily-controlled reaction conditions.
Embodiment 1
50.0g pentyne acetoacetic ester (1.0eq, 0.396mol) is added in reaction flask S1, addition 141.15g (1.5eq,
Acetonitrile 750mL, room temperature are added into above-mentioned reaction flask for 0.594mol) N- (methoxyl methyl)-N- (trimethyl silicane methyl) benzylamine
Under, it is added dropwise to concentrated hydrochloric acid/aqueous solution 3.8g/20ml(0.1eq, 0.0396mol), about 30min is added dropwise.Holding room temperature 20 ~
25 DEG C of reaction 16h.
Post-processing: after reaction, concentration removal acetonitrile is added ethyl acetate 700ml, uses saturated aqueous solution of sodium bicarbonate
It washes twice (250mL × 2), then washed once (250mL × 1) with sodium-chloride water solution；Organic phase is evaporated under reduced pressure to no fraction
Generate (40 ~ 50 DEG C, -0.1Mpa), directly with enter next step.
Reaction equation are as follows:
。
S2, by previous step crude Compound A(1.0eq, 0.396mol), 1500mL methylene chloride puts into reaction flask, stirs
It mixes to dissolved clarification；Chloro-carbonic acid 2- chloroethene ester 169.84g(3.0eq, 1.188mol are added at 0 DEG C), it is kept stirring uniformly.In being warming up to
It warm 20-25 DEG C, is stirred to react 1-2 hours；TLC is detected without raw material point；
(20-25 DEG C) 100mL methanol is added into product under room temperature；40 DEG C are heated to react 6 hours；TLC is detected without raw material
Point；
Post-processing: (40-50 DEG C, -0.1Mpa) of evaporated under reduced pressure obtains crude product, directly carries out in next step.
Reaction equation are as follows:
。
S3 in the reaction flask of previous step crude compound B (1.0eq, 0.396mol), is added 500mL acetone and is kept stirring,
Nitrogen protection.Ice-water bath is cooled to 0 DEG C, is added triethylamine 119.98g (3.0eq, 1.188mol), keeps that CbzCl is added at 0 DEG C
(101.33g, 1.5eq, 0.594mol)/acetone (400ml) solution, about 1h are added dropwise, then are warming up to 25 DEG C of interior temperature reactions
1h。
Post-processing: being added tap water 400ml quenching reaction, and 40 ~ 45 DEG C of reduced pressures remove solvent acetone, acetic acid second is added
Ester 800ml, layering remove water phase, and organic phase uses tap water 400ml extraction primary again, and organic phase evaporated under reduced pressure to no fraction produces
Raw, crude product directly carries out in next step.
Reaction equation are as follows:
。
In the reaction flask of previous step crude reaction compound C, 300mL methanol is added in S4, and being kept stirring makes to dissolve, cooling
To about 0-5 DEG C of interior temperature, it is added dropwise in the 1N lithium hydroxide aqueous solution investment reaction flask of 20ml, stirring keeps room temperature reaction about
4h；
TLC detects fully reacting；
Post-processing: removing most of methanol under reduced pressure, and 200mL ethyl acetate is added and 100ml water stirs 10 minutes, is layered, removes
Ethyl acetate phase；500mL ethyl acetate is added under ice bath in water phase, adjusts water phase pH to 4 with concentrated hydrochloric acid；Layering, water phase are used again
The extraction of 200mL ethyl acetate is primary, merges organic phase, and organic phase is concentrated under reduced pressure into no fraction and generates；100ml methanol, ice is added
Bath lower stirring 3 hours, there is solid precipitation；Filtering, collects solid, and 45 DEG C of solid decompression dryings obtain product 43g, four step total recoverys
39.4%。
Reaction equation are as follows:
。
Previous step product 42.75g(1.0eq, 0.156mol) is added in hydrogen reaction kettle S5, addition 1.4g (
0.025eq, 0.004mol) (solvent methanol 600ml is added in S-segphos Ru (OAc) 2 to catalyst, and diisopropylamine is added
47.27g(3.0eq, 0.468mol), it is kept stirring uniformly, nitrogen is replaced 3 times, then logical hydrogen is replaced 3 times, and Hydrogen Vapor Pressure is increased
To 2.0MPa, keep reacting 6h at 30 DEG C of temperature；
Post-processing: after fully reacting, displacement nitrogen displacement removal hydrogen, diatomite is filtered, and filter cake is washed with methanol (100ml*3)
Three times；Mother liquor evaporated under reduced pressure obtains 39g colourless oil liquid.
Reaction equation are as follows:
。
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization, feature
It is, comprising the following steps:
S1, using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material, in a solvent
Intermediate condensation midbody product compound A, the structural formula of the compound A are prepared through being condensed ring closure reaction under acid catalysis
Are as follows:
；
Compound A is added in solvent by S2, stirring, and after 0 ~ 5 DEG C of addition ethyl chloroformate, 1 ~ 2h is reacted at 20 ~ 25 DEG C
Afterwards, alcohols solvent is added, the reaction was continued at 40 ~ 90 DEG C, obtains midbody product compound B, the structural formula of the compound B
Are as follows:
；
S3, under the conditions of alkali, compound B prepares N protection intermediates through acylation reaction with benzyl chloroformate in a solvent and produces
Compounds C, the structural formula of the compound C are as follows:
；
S4, under alkaline condition, compound C prepares midbody product compound D, describedization through ester hydrolysis reaction in a solvent
Close the structural formula of object D are as follows:
；
Compound D is crystallized to obtain intermediate sterling through processing by S5, in a solvent, under the conditions of catalyst is existing, is passed through with hydrogen
Asymmetric reduction reaction obtains (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
2. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1
The synthetic method of acid, characterized in that the valerylene acid esters in the S1 is valerylene acid methyl esters, valerylene acetoacetic ester or valerylene
One of tert-butyl acrylate；
The R1For methyl, ethyl or tert-butyl；
Solvent in the S1 is ethyl acetate, in acetonitrile, toluene, acetone, methylene chloride, chloroform, 1,2- dichloroethanes
It is any or a combination thereof；
Acid in the S1 be any one of acetic acid, methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid or
A combination thereof.
3. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N-suitable for industrialization according to claim 1 or 2
The synthetic method of 3- carboxylic acid, characterized in that valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) in the S1
Benzyl amine equivalents ratio is 0.8:1 ~ 1:2.
4. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1
The synthetic method of acid, characterized in that the reaction temperature in the S1 is -5 ~ 50 DEG C.
5. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1
The synthetic method of acid, characterized in that solvent is ethyl acetate, acetonitrile, toluene, acetone, methylene chloride, three chloromethanes in the S2
Any one of alkane, 1,2- dichloroethanes or a combination thereof；The equivalents ratio of compound A and ethyl chloroformate is in the S2
(0.8 ~ 1): (1 ~ 5)；
Alcohols solvent is one of methanol, ethyl alcohol, isopropanol or combinations thereof in the S2.
6. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1
The synthetic method of acid, characterized in that the solvent in the S3 is ethyl acetate, acetonitrile, toluene, acetone, methylene chloride and water
Any one of or a combination thereof；
Alkali in the S3 is any one of triethylamine, DBU, sodium carbonate, potassium carbonate, potassium hydroxide, saleratus or its group
It closes；
The equivalents ratio that feeds intake of the compound B and benzyl chloroformate is (0.8 ~ 1): (1 ~ 5).
7. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1
The synthetic method of acid, characterized in that solvent in the S4 be acetonitrile, toluene, acetone, methylene chloride, 1,2- dioxane with
And any one of water or a combination thereof；
Alkali in the S4 be potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, DBU, potassium hydroxide, lithium hydroxide,
In sodium methoxide, sodium ethoxide any one or combinations thereof；
The throwing amount equivalents ratio of the compound C and alkali is (0.8 ~ 1): (1 ~ 5).
8. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1
The synthetic method of acid, characterized in that the solvent in the S5 is toluene, acetone, methylene chloride, 1,2- dioxane, methanol, second
Any one of alcohol, isopropanol, benzyl alcohol and water or a combination thereof；
Alkali in the S5 is triethylamine, diisopropyl ethyl amine, diisopropylamine, DBU, potassium hydroxide, appointing in lithium hydroxide
It anticipates one kind or combinations thereof；
The throwing amount equivalents ratio of compound D and alkali in the S5 are 1:(1 ~ 10).
9. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 8
The synthetic method of acid, characterized in that the throwing amount equivalents ratio of the compound D and catalyst is 1:(0.001 ~ 0.3).
10. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N-suitable for industrialization according to claim 8 or claim 9
The synthetic method of 3- carboxylic acid, characterized in that the catalyst is S-segphos Ru (OAc) 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910498948.7A CN110183367A (en) | 2019-06-11 | 2019-06-11 | A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910498948.7A CN110183367A (en) | 2019-06-11 | 2019-06-11 | A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110183367A true CN110183367A (en) | 2019-08-30 |
Family
ID=67721072
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910498948.7A Pending CN110183367A (en) | 2019-06-11 | 2019-06-11 | A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110183367A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110615753A (en) * | 2019-09-02 | 2019-12-27 | 南京新酶合医药科技有限公司 | Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid |
| CN111454189A (en) * | 2020-05-12 | 2020-07-28 | 苏州旺山旺水生物医药有限公司 | Synthetic method of sepiatinib intermediate |
| CN112538010A (en) * | 2019-09-20 | 2021-03-23 | 凯特立斯（深圳）科技有限公司 | Preparation method of key intermediate for synthesizing artemisinin compound |
| CN118047785A (en) * | 2024-03-07 | 2024-05-17 | 和鼎（南京）医药技术有限公司 | Method for preparing Wu Pati Ni and intermediate thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070638A (en) * | 2009-11-24 | 2011-05-25 | 上海药明康德新药开发有限公司 | Preparation method of hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative |
| CN109705011A (en) * | 2019-01-18 | 2019-05-03 | 浙江师范大学 | A kind of synthetic method and intermediate of Upatinib intermediate |
-
2019
- 2019-06-11 CN CN201910498948.7A patent/CN110183367A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070638A (en) * | 2009-11-24 | 2011-05-25 | 上海药明康德新药开发有限公司 | Preparation method of hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative |
| CN109705011A (en) * | 2019-01-18 | 2019-05-03 | 浙江师范大学 | A kind of synthetic method and intermediate of Upatinib intermediate |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110615753A (en) * | 2019-09-02 | 2019-12-27 | 南京新酶合医药科技有限公司 | Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid |
| CN112538010A (en) * | 2019-09-20 | 2021-03-23 | 凯特立斯（深圳）科技有限公司 | Preparation method of key intermediate for synthesizing artemisinin compound |
| CN112538010B (en) * | 2019-09-20 | 2023-08-11 | 凯特立斯（深圳）科技有限公司 | Preparation method of artemisinin compound synthesized key intermediate |
| CN111454189A (en) * | 2020-05-12 | 2020-07-28 | 苏州旺山旺水生物医药有限公司 | Synthetic method of sepiatinib intermediate |
| CN111454189B (en) * | 2020-05-12 | 2021-11-23 | 苏州旺山旺水生物医药有限公司 | Synthetic method of sepiatinib intermediate |
| CN118047785A (en) * | 2024-03-07 | 2024-05-17 | 和鼎（南京）医药技术有限公司 | Method for preparing Wu Pati Ni and intermediate thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110183367A (en) | A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization | |
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN109705011B (en) | A kind of synthetic method and intermediate of Upatinib intermediate | |
| CN105198775B (en) | A kind of preparation method of chiral N Boc biphenyl Propanolamines | |
| EP3828170A1 (en) | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene | |
| RU2730006C1 (en) | Method of producing 5r-[(benzyloxy)amino]piperidine-2s-carboxylic acid or derivative thereof | |
| CN102757431B (en) | A kind of novel method of synthesizing sitagliptin | |
| CN110615753A (en) | Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid | |
| CN104387299B (en) | The preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide | |
| EP2914574B1 (en) | New process | |
| US8912345B2 (en) | Method for preparing optically pure (−)-clausenamide compound | |
| CN105524042B (en) | A method of preparing bent Ge Lieting | |
| JP6137185B2 (en) | (R) -1,1,3-Trimethyl-4-aminoindane production method | |
| CN104837817B (en) | Synthetic route for preparation of 3-amino-piperidine compounds | |
| CN110015978B (en) | Synthesis method of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine | |
| CN103304447A (en) | Synthesis process of (S)-rivastigmine | |
| CN115010638B (en) | Synthesis method of Nemactetvir intermediate | |
| CN110183368A (en) | The synthetic method of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization | |
| CN109810059A (en) | A kind of preparation method of left-handed hydrochloric acid demethyl benzene ring pelargonate | |
| CN102250005B (en) | Preparation method of Eslicarbazepine | |
| CN104974051A (en) | Synthetic method for (1S,4R)-cis-4-amino-2-cyclopentene-1-methanol hydrochloride | |
| CN101298448B (en) | Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol | |
| CN104530112A (en) | Method for preparing everolimus intermediate and ethylated impurities thereof | |
| CN106699592A (en) | Method for preparing lisinopril intermediate | |
| CN103288813A (en) | Preparation method of aprepitant |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190830 |
|
| WD01 | Invention patent application deemed withdrawn after publication |