CN103274943B - 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate and preparation method thereof - Google Patents
4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate and preparation method thereof Download PDFInfo
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- CN103274943B CN103274943B CN201310196966.2A CN201310196966A CN103274943B CN 103274943 B CN103274943 B CN 103274943B CN 201310196966 A CN201310196966 A CN 201310196966A CN 103274943 B CN103274943 B CN 103274943B
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- butyl
- dioxo
- benzoic ether
- normal
- propynyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 229960000214 pralatrexate Drugs 0.000 claims abstract description 18
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 claims abstract description 17
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007259 addition reaction Methods 0.000 claims abstract description 5
- 238000005837 enolization reaction Methods 0.000 claims abstract description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims abstract 3
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 20
- -1 phenyl aldehyde Chemical class 0.000 claims description 18
- 239000007822 coupling agent Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- PZRKPUQWIFJRKZ-UHFFFAOYSA-N pyrimidine-2,4,5,6-tetramine Chemical compound NC1=NC(N)=C(N)C(N)=N1 PZRKPUQWIFJRKZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims description 4
- VEZUQRBDRNJBJY-UHFFFAOYSA-N cyclohexanone oxime Chemical compound ON=C1CCCCC1 VEZUQRBDRNJBJY-UHFFFAOYSA-N 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 4
- YGRFXPCHZBRUKP-UHFFFAOYSA-N Methoxamine hydrochloride Chemical compound Cl.COC1=CC=C(OC)C(C(O)C(C)N)=C1 YGRFXPCHZBRUKP-UHFFFAOYSA-N 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229960004269 methoxamine hydrochloride Drugs 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 2
- ZGUQGPFMMTZGBQ-UHFFFAOYSA-N [Al].[Al].[Zr] Chemical compound [Al].[Al].[Zr] ZGUQGPFMMTZGBQ-UHFFFAOYSA-N 0.000 claims description 2
- NDVFUVDXDDUZCH-UHFFFAOYSA-N [SiH4].[N-]=[N+]=[N-] Chemical compound [SiH4].[N-]=[N+]=[N-] NDVFUVDXDDUZCH-UHFFFAOYSA-N 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 2
- UQZIWOQVLUASCR-UHFFFAOYSA-N alumane;titanium Chemical compound [AlH3].[Ti] UQZIWOQVLUASCR-UHFFFAOYSA-N 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- VGYYSIDKAKXZEE-UHFFFAOYSA-L hydroxylammonium sulfate Chemical compound O[NH3+].O[NH3+].[O-]S([O-])(=O)=O VGYYSIDKAKXZEE-UHFFFAOYSA-L 0.000 claims description 2
- WJZHMLNIAZSFDO-UHFFFAOYSA-N manganese zinc Chemical compound [Mn].[Zn] WJZHMLNIAZSFDO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 2
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 2
- NDKWCCLKSWNDBG-UHFFFAOYSA-N zinc;dioxido(dioxo)chromium Chemical compound [Zn+2].[O-][Cr]([O-])(=O)=O NDKWCCLKSWNDBG-UHFFFAOYSA-N 0.000 claims description 2
- OWOHLURDBZHNGG-YFKPBYRVSA-N (8ar)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione Chemical group O=C1CNC(=O)[C@@H]2CCCN12 OWOHLURDBZHNGG-YFKPBYRVSA-N 0.000 claims 2
- GXDVEXJTVGRLNW-UHFFFAOYSA-N [Cr].[Cu] Chemical compound [Cr].[Cu] GXDVEXJTVGRLNW-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 abstract 3
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 abstract 1
- 229940120731 pyruvaldehyde Drugs 0.000 abstract 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940095102 methyl benzoate Drugs 0.000 description 6
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 0 *Nc(nc1N)nc2c1nc(CC(CC#C)c(cc1)ccc1C(NCCCC(O)=O)=O)cn2 Chemical compound *Nc(nc1N)nc2c1nc(CC(CC#C)c(cc1)ccc1C(NCCCC(O)=O)=O)cn2 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 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 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- CRZQGDNQQAALAY-UHFFFAOYSA-N Me ester-Phenylacetic acid Natural products COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910001115 Zinc-copper couple Inorganic materials 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 244000144992 flock Species 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940029263 pralatrexate injection Drugs 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel medical compound 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate (I) and a preparation method thereof. The preparation method comprises the following steps of carrying out an addition reaction on 4-carbalkoxy benzaldehyde (II) and 3-propargyl bromide (III) to generate 4-(1-hydroxyl-3-butyne) benzoate (IV); and carrying out a coupled reaction on an intermediate (IV) and pyruvaldehyde dialkyl acetal (V) after being subjected to enolization under the action of a metal catalyst to form the 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate (I). According to the intermediate (I) and the preparation method thereof, a novel preparation way for the antineoplastic pralatrexate is provided and the economic and technological development of the pralatrexate is promoted.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of new compound 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] benzoic ether and preparation method thereof.
Background technology
Pralatrexate (Pralatrexate) is the medicine being used for the treatment of recurrent and intractable lymphoma peripheral T cell developed by U.S. A Luosi treatment company (Allos Therapeutics Inc).Pralatrexate injection is in Nikkei U.S. FDA approval September 24 in 2009 in U.S.'s listing, and commodity are called Folotvn.The chemistry of Pralatrexate is called N-[4-(1-(2,4-diamino-6-pteridine) methyl-3-butynyl) benzoyl]-Pidolidone.
A Luosi treats preparation method and the pharmaceutical use that the former United States Patent (USP) ground of company No. US6028071, No. US2010248249 and No. US2011111436 and No. WO2012061469th, world patent report Pralatrexate.The method is for raw material with 4-methoxycarbonyl methyl phenylacetate (VIII), replace with 3-propargyl bromide and generate 4-(1-carboxylate methyl ester-3-butine) methyl benzoate (IX), there is nucleophilic substitution reaction and generate 4-[1-(2 in intermediate (IX) and 6-brooethyl-2.4-diamino dish pyridine (X), 4-diamino-6-pteridine) methyl isophthalic acid-carboxylate methyl ester-3-butynyl] methyl benzoate (XI), intermediate (XI) generates 4-[1-(2 by alkaline hydrolysis decarboxylation, 4-diamino-6-pteridine) methyl-3-butynyl] phenylformic acid (Pralatrexate phenylformic acid, VII), Pralatrexate phenylformic acid (VII) and the condensation of Pidolidone diethyl ester generate Pralatrexate diethyl ester (XII), intermediate (XII) generates Pralatrexate through being hydrolyzed de-ester again.
Similar with the synthetic method of other folic acid antagonist as aminopterin, methotrexate, pemetrexed, above-mentioned syntheti c route is benzoic ether (IX) condensation replaced by dish pyridine female ring (X) and 4-position, obtain key intermediate Pralatrexate phenylformic acid (VII) through the step such as decarboxylation, hydrolysis again, intermediate (VII) and the condensation of Pidolidone diethyl ester also can obtain Pralatrexate through being hydrolyzed.Although the method can obtain target compound Pralatrexate, due to factors such as raw material is rare, step is more, separation difficulty, thus hinder the suitability for industrialized production of this product.Seek more succinct and more economical synthesis path, particularly by novel technological design, avoid using rare intermediate 6-brooethyl-2.4-diamino dish pyridine (X), directly obtained pula phenylformic acid (VII), the economic technology development for Pralatrexate bulk drug has important practical significance.
Summary of the invention
The object of the invention is to seek new prepare approach, according to the Atom economy synthesis theory of Green Chemistry, a kind of new medicine intermediate 4-[1-(2-propynyl)-3 is provided, 4-dioxo normal-butyl] benzoic ether (I) and preparation method thereof, pula phenylformic acid (VII) can be obtained easily by this intermediate, whole technological process is succinct, economy and environmental protection, is beneficial to suitability for industrialized production.
To achieve these goals, the invention provides a kind of medicine intermediate 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] benzoic ether (I), it is characterized in that chemical formula is such as formula shown in (I):
In addition, the present invention also comprises following attached technical scheme:
R in described formula (I) compound 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] benzoic ether
1for the phenyl of the aliphatic group of 1-10 carbon atom, phenyl and replacement.
Described formula (I) compound 4-[1-(in 2-alkynyl)-3,4-dioxo normal-butyl] benzoic ether, its preparation method comprises and with 4-carbalkoxy phenyl aldehyde (II) and 3-propargyl bromide (III), addition reaction occurs and generate intermediate 4-(1-hydroxyl-3-butine) benzoic ether (IV); Linked reaction is there is and generates 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] benzoic ether (I) in intermediate (IV) and pyruvic aldehyde dialkyl acetal (V) under metal catalyst effect.
Described compound 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] benzoic ether (I) and preparation method thereof, the alkyl R in its raw material 4-carbalkoxy benzoic ether (II) and corresponding intermediate 4-(1-hydroxyl-3-butine) benzoic ether (IV)
1for phenyl, preferable methyl or the ethyl of the aliphatic hydrocarbon of 1-10 carbon atom, phenyl or replacement.
Alkyl R in described raw material acetone aldehyde dialkyl acetal (V)
2for methyl, ethyl, propyl group, allyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, 1,2-ethyl group or fork acetonyl, preferable methyl or fork acetonyl.
The catalyzer of described addition reaction is zinc-copper coupling agent, aluminum-zirconium coupling agent, zinc chrome coupling agent, chromium coupling agent processed, aluminium titanium coupling agent or zinc-manganese coupling agent, preferred zinc-copper coupling agent.
The enolization reagent of described linked reaction is Trimethlyfluorosilane, trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, trimethylammonium cyanoalkysilane, trimethyl azide silane or trimethylsilyl triflate, preferred trimethylsilyl triflate.
Described compound 4-[1-(in 2-alkynyl)-3,4-dioxo normal-butyl] benzoic ether (I) may be used for the key intermediate 4-[1-(2 preparing antitumour drug Pralatrexate, 4-diamino-6-pteridine) methyl-3-butynyl] phenylformic acid (abbreviation pula phenylformic acid, VII), its reactions steps comprises with compound 4-[1-(in 2-alkynyl)-3,4-dioxo normal-butyl] benzoic ether (I) and 2,4,5,6-tetraminopyrimidine (VI) obtains pula phenylformic acid (VII) through cyclization and alkaline hydrolysis.
The oximate agent used of described ring-closure reaction is oxammonium hydrochloride, oxammonium sulfate, methoxamine hydrochloride, cyclohexanone-oxime or acetoxime, preferred methoxamine hydrochloride or acetoxime.
Compared to prior art, new compound 4-[1-(2-propynyl)-3 involved in the present invention, 4-dioxo normal-butyl] benzoic ether and preparation method thereof, this compound can be used for key intermediate 4-[1-(2 prepared by preparation Pralatrexate, 4-diamino-6-pteridine) methyl-3-butynyl] phenylformic acid (VII), the preparation process that can make Pralatrexate by this intermediate (VII) is more succinct, economy and environmental protection, be beneficial to suitability for industrialized production, promote the economy of this bulk drug and the development of technology.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
Embodiment one:
Under drying and nitrogen atmosphere, in there-necked flask, add the tetrahydrofuran solution 25mL containing the even 3.5g of zinc system.The solution that 4-methoxycarbonyl phenyl aldehyde (II) (3.28g, 20mmol), 3-propargyl bromide (III) (2.93g, 25mmol) and anhydrous tetrahydro furan 25mL form is dripped under vigorous stirring.Slowly be warming up to system backflow, keep backflow 2 hours, TLC detection reaction terminates.Be down to room temperature, add dilute hydrochloric acid cancellation reaction, be extracted with ethyl acetate, anhydrous sodium sulfate drying.Decompression, with receiving solvent, obtains pale yellow oil 4-(1-hydroxyl-3-butine) methyl benzoate (IV) 3.48g, yield 85.3%.
Embodiment two:
Under drying and nitrogen atmosphere, in there-necked flask, add the tetrahydrofuran solution 25mL containing zinc copper couple 3.5g.The solution that in 4-ethoxycarbonyl phenyl aldehyde (II) (3.56g, 20mmol), 3-bromine, alkynes (III) (2.93g, 25mmol) and anhydrous tetrahydro furan 25mL form is dripped under vigorous stirring.Slowly be warming up to system cocurrent flow, keep cocurrent flow 2 hours, TLC detection reaction terminates.Be down to room temperature, add dilute hydrochloric acid cancellation reaction, be extracted with ethyl acetate, anhydrous sodium sulfate drying.Decompression, with receiving solvent, obtains pale yellow oil 4-(1-hydroxyl-3-butine) ethyl benzoate (IV) 3.68g, yield 84.4%.
Embodiment three:
Under nitrogen protection, in there-necked flask, add pyruvic aldehyde dimethyl acetal (V) (4.72g, 40mmol), triethylamine (5.5g, 54mmol) and tetrahydrofuran (THF) 50mL.Be cooled to 0 DEG C, under stirring, drip trifluoromethanesulfonic acid trimethylsilane ester (10mL, 50mmol), drip and finish, room temperature reaction 4 hours, TLC detection reaction terminates.Add normal hexane, stir after 15 minutes, solids removed by filtration.Mother liquor uses water, water and brine It successively, anhydrous magnesium sulfate drying, vacuum distillation recovered solvent.The flaxen oily matter 100mL methylene dichloride obtained dissolves and is placed in dry there-necked flask, adds 4-(1-hydroxyl-3-butine) methyl benzoate (IV) (2.04g, 10mmol).Be cooled to-65 DEG C, under nitrogen protection, drip the dichloromethane solution 7mL of 1M tin tetrachloride, drip and finish, keep this thermotonus 15 minutes.By reaction solution impouring saturated aqueous common salt, be warming up to 50 DEG C, stir 30 minutes, leave standstill, separate organic phase.Organic phase uses 5% sodium bicarbonate, water and brine It successively, anhydrous sodium sulfate drying, concentrating under reduced pressure.Give light yellow oil 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] methyl benzoate (I) 1.68g, yield is 65.1%.
Embodiment four:
Under nitrogen protection, in there-necked flask, add pyruvic aldehyde dimethyl acetal (V) (4.72g, 40mmol), triethylamine (5.5g, 54mmol) and tetrahydrofuran (THF) 50mL.Be cooled to 0 DEG C, under stirring, drip trifluoromethanesulfonic acid trimethylsilane ester (10mL, 50mmol), drip and finish, room temperature reaction 4 hours, TLC detection reaction terminates.Add normal hexane, stir after 15 minutes, solids removed by filtration.Mother liquor uses water, water and brine It successively, anhydrous magnesium sulfate drying, and underpressure distillation is with receiving solvent.The flaxen oily matter 100mL methylene dichloride obtained dissolves and is placed in dry there-necked flask, adds 4-(1-hydroxyl-3-butine) ethyl benzoate (IV) (2.18g, 10mmol).Be cooled to-65 DEG C, under nitrogen protection, drip the dichloromethane solution 7mL of 1M tin tetrachloride, drip and finish, keep this thermotonus 15 minutes.By reaction solution impouring saturated aqueous common salt, be warming up to 50 DEG C, stir 30 minutes, leave standstill, separate organic phase.Organic phase uses 5% sodium bicarbonate, water and brine It successively, and anhydrous thin sour sodium is dry, concentrating under reduced pressure.Give light yellow oil 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] ethyl benzoate (I) 1.80g, yield is 66.2%.
Embodiment five:
4-[1-(in 2-alkynyl)-3 is added in three mouthfuls of reaction flasks, 4-dioxo normal-butyl] methyl benzoate (I) (1.22g, 6mmol), interior ketoxime (0.51g, 7mmol) with distilled water 50mL, drip the dilute hydrochloric acid of 1N, the pH value regulating reaction system is 2-3.Be warming up to 50-60 DEG C, stirring reaction 2 hours.Be down to room temperature, add 2,4,5,6-tetraminopyrimidine (VI) (0.70g, 5mmol), first room temperature reaction 4 hours, then be warming up to back flow reaction 6 hours, have light yellow flocks to occur.Regulate pH to neutral with saturated sodium bicarbonate solution, cooling crystallization, filter, gained solid joins in the sodium hydroxide solution of 20%, is warming up to 50 DEG C, reacts 4 hours, and TLC detects hydrolysis completely.Cooling, regulates pH to 2-3 with dilute hydrochloric acid, cooling crystallization, filter, dry, obtain off-white color solid 4-[1-(2,4-diamino-6-pteridine) methyl-3-butynyl] phenylformic acid (pula phenylformic acid, VII) 1.60g, yield is 92.0%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (8)
1. compound 4-[1-(2-propynyl)-3, a 4-dioxo normal-butyl] benzoic ether (I), is characterized in that chemical formula is such as formula shown in (I):
R in described formula (I) compound
1for aliphatic hydrocarbon or the phenyl of 1-10 carbon atom.
2. compound 4-[1-(2-propynyl)-3 as claimed in claim 1,4-dioxo normal-butyl] preparation method of benzoic ether (I), it is characterized in that: its preparation method comprises and with 4-carbalkoxy phenyl aldehyde (II) and 3-propargyl bromide (III), addition reaction occurs and generate intermediate 4-(1-hydroxyl-3-butine) benzoic ether (IV); Described intermediate (IV) and pyruvic aldehyde dialkyl acetal (V) are by the enolization of carbonyl and linked reaction occurs under tin tetrachloride effect generate 4-[1-(2-propynyl)-3,4-dioxo normal-butyl] benzoic ether (I).
3. compound 4-[1-(2-propynyl)-3 as claimed in claim 2,4-dioxo normal-butyl] preparation method of benzoic ether (I), it is characterized in that: the alkyl R in described raw material 4-carbalkoxy phenyl aldehyde (II) and corresponding intermediate 4-(1-hydroxyl-3-butine) benzoic ether (IV)
1for aliphatic hydrocarbon or the phenyl of 1-10 carbon atom.
4. compound 4-[1-(2-propynyl)-3 as claimed in claim 2,4-dioxo normal-butyl] preparation method of benzoic ether (I), it is characterized in that: the alkyl R2 in described raw material acetone aldehyde dialkyl acetal (V) is methyl, ethyl, propyl group, allyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, 1,2-ethyl group or fork acetonyl.
5. compound 4-[1-(2-propynyl)-3 as claimed in claim 2,4-dioxo normal-butyl] preparation method of benzoic ether (I), it is characterized in that: the catalyzer of described addition reaction is zinc-copper coupling agent, aluminum-zirconium coupling agent, zinc chrome coupling agent, copper chromium coupling agent, aluminium titanium coupling agent or zinc-manganese coupling agent.
6. compound 4-[1-(2-propynyl)-3 as claimed in claim 2,4-dioxo normal-butyl] preparation method of benzoic ether (I), it is characterized in that: the enolization reagent of described linked reaction is Trimethlyfluorosilane, trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, trimethylammonium cyanoalkysilane, trimethyl azide silane or trimethylsilyl triflate.
7. compound 4-[1-(2-propynyl)-3 as claimed in claim 1,4-dioxo normal-butyl] benzoic ether (I), it is characterized in that itself and 2,4,5,6-tetraminopyrimidine (VI) can obtain key intermediate 4-[1-(2, the 4-diamino-6-pteridine) methyl-3-butynyl] phenylformic acid (VII) of antitumour drug Pralatrexate through ring-closure reaction and alkaline hydrolysis.
8. compound 4-[1-(2-propynyl)-3 as claimed in claim 7,4-dioxo normal-butyl] benzoic ether (I), it is characterized in that: the oximate agent used of described ring-closure reaction is oxammonium hydrochloride, oxammonium sulfate, methoxamine hydrochloride, cyclohexanone-oxime or acetoxime.
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