US20220267291A1 - Process for preparing esters of n-acylated amino acids with acid-labile keto protective group functions - Google Patents
Process for preparing esters of n-acylated amino acids with acid-labile keto protective group functions Download PDFInfo
- Publication number
- US20220267291A1 US20220267291A1 US17/743,534 US202217743534A US2022267291A1 US 20220267291 A1 US20220267291 A1 US 20220267291A1 US 202217743534 A US202217743534 A US 202217743534A US 2022267291 A1 US2022267291 A1 US 2022267291A1
- Authority
- US
- United States
- Prior art keywords
- sodium
- methyl
- potassium
- radical
- formula
- 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.)
- Abandoned
Links
- 150000001413 amino acids Chemical class 0.000 title abstract description 18
- 125000006239 protecting group Chemical group 0.000 title abstract description 8
- 229930194542 Keto Natural products 0.000 title abstract description 7
- 125000000468 ketone group Chemical group 0.000 title abstract description 7
- 150000002148 esters Chemical class 0.000 title abstract description 6
- 238000004519 manufacturing process Methods 0.000 title description 7
- 238000000034 method Methods 0.000 claims abstract description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 22
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 22
- 235000002639 sodium chloride Nutrition 0.000 claims description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 description 15
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 15
- 229960003975 potassium Drugs 0.000 claims description 15
- 239000011591 potassium Chemical group 0.000 claims description 15
- 229910052700 potassium Chemical group 0.000 claims description 15
- 239000011734 sodium Substances 0.000 claims description 15
- 229910052708 sodium Inorganic materials 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
- 235000017550 sodium carbonate Nutrition 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000000460 chlorine Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000011736 potassium bicarbonate Substances 0.000 claims description 9
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 9
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 235000011181 potassium carbonates Nutrition 0.000 claims description 9
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 9
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 9
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003880 polar aprotic solvent Substances 0.000 abstract description 5
- 230000032050 esterification Effects 0.000 abstract description 4
- 238000005886 esterification reaction Methods 0.000 abstract description 4
- 150000001350 alkyl halides Chemical class 0.000 abstract description 3
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- -1 amino acid esters Chemical class 0.000 description 29
- 239000000243 solution Substances 0.000 description 25
- 239000000203 mixture Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 0 *OC(=O)C1(NC(=O)C[2*])CCC([3*])([4*])CC1 Chemical compound *OC(=O)C1(NC(=O)C[2*])CCC([3*])([4*])CC1 0.000 description 6
- BSYPPFKBABAJKX-UHFFFAOYSA-N 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride Chemical compound CC1=CC(Cl)=CC(C)=C1CC(Cl)=O BSYPPFKBABAJKX-UHFFFAOYSA-N 0.000 description 6
- RATNFZKRNGZLPX-UHFFFAOYSA-N 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid Chemical compound ClC1=CC(=C(C(=C1)C)CC(=O)NC1(CCC2(OCCO2)CC1)C(=O)O)C RATNFZKRNGZLPX-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- KVRPHYIOKYTCEF-UHFFFAOYSA-N methyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound C1CC(C(=O)OC)(NC(=O)CC=2C(=CC(Cl)=CC=2C)C)CCC21OCCO2 KVRPHYIOKYTCEF-UHFFFAOYSA-N 0.000 description 6
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 230000002152 alkylating effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Chemical group 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 239000003444 phase transfer catalyst Substances 0.000 description 4
- RJWSHUWMLOVFEF-UHFFFAOYSA-M sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound NC1(CCC2(OCCO2)CC1)C(=O)[O-].[Na+] RJWSHUWMLOVFEF-UHFFFAOYSA-M 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- JGDXDPYHIIUBEM-UHFFFAOYSA-N 2-(4-chloro-2,6-dimethylphenyl)acetic acid Chemical compound CC1=CC(Cl)=CC(C)=C1CC(O)=O JGDXDPYHIIUBEM-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- CMURKFSRGAWINZ-UHFFFAOYSA-N 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy-9,12-dioxa-4-azadispiro[4.2.4^{8}.2^{5}]tetradec-1-en-3-one Chemical compound CC1=CC(Cl)=CC(C)=C1C(C(N1)=O)=C(O)C11CCC2(OCCO2)CC1 CMURKFSRGAWINZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- KKWUACQXLWHLCX-UHFFFAOYSA-N hydron;tetradecan-1-amine;chloride Chemical compound Cl.CCCCCCCCCCCCCCN KKWUACQXLWHLCX-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229940078552 o-xylene Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010966 qNMR Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 2
- SNNIPOQLGBPXPS-UHFFFAOYSA-M tetraoctylazanium;chloride Chemical compound [Cl-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC SNNIPOQLGBPXPS-UHFFFAOYSA-M 0.000 description 2
- AKUNSPZHHSNFFX-UHFFFAOYSA-M tributyl(tetradecyl)phosphanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC AKUNSPZHHSNFFX-UHFFFAOYSA-M 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ANMHSVYERDQKIP-UHFFFAOYSA-N CC(=O)C1(N)CCC2(CC1)OCCO2 Chemical compound CC(=O)C1(N)CCC2(CC1)OCCO2 ANMHSVYERDQKIP-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- FUXWZHVFRIXGTD-UHFFFAOYSA-M potassium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound NC1(CCC2(OCCO2)CC1)C(=O)[O-].[K+] FUXWZHVFRIXGTD-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- XNXGDVAUUNSOOG-UHFFFAOYSA-M sodium 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound ClC1=CC(=C(C(=C1)C)CC(=O)NC1(CCC2(OCCO2)CC1)C(=O)[O-])C.[Na+] XNXGDVAUUNSOOG-UHFFFAOYSA-M 0.000 description 1
- 238000010099 solid forming Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 150000003470 sulfuric acid monoesters Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- BRKFQVAOMSWFDU-UHFFFAOYSA-M tetraphenylphosphanium;bromide Chemical compound [Br-].C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BRKFQVAOMSWFDU-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel process for preparing esters of N-acylated amino acids from N-acylated amino acids which contain an acid-labile keto protective group and readily available organic alkylating reagents.
- the esters of N-acylated amino acids serve as precursors for the preparation of crop protection compositions with insecticidal, acaricidal or herbicidal action (for example WO 06/089633).
- the present invention provides a novel process for preparing compounds of the general formula (I)
- alkylating reagents use may be made of alkyl halides of the general formula (V) or sulfuric acid di- or monoesters or salts of the sulfuric acid monoester of the general formula (VI)
- the compounds of the formula (II) and (III) are either commercially available or can be prepared by known processes.
- Y is fluorine or chlorine
- the present invention likewise provides novel compounds of the general formula (I-a)
- the present invention likewise provides novel compounds of the general formula (IV-1)
- firstly amino acid salts of the general formula (II) are dissolved in water or an aqueous solution of a base or these amino acid salts of the general formula (II) are produced by the corresponding free amino acids or salts of the amino acids being dissolved with acids such as hydrochlorides, sulfates or hydrosulfates in an aqueous solution of a base.
- useful bases include lithium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide or mixtures of these bases.
- Use is preferably made of sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide or mixtures of these bases.
- the amount of base is selected such that a pH of 8 to 14 is established.
- a pH of 10.5 to 12.5 is established.
- inorganic acids include hydrochloric acid or sulfuric acid, preferably hydrochloric acid.
- the amount of carbonyl halide of the general formula (III) in this case is 0.9 to 1.5 molar equivalents, based on the amino acid salt of the general formula (II). Preference is given to using 1.0 to 1.25 molar equivalents.
- the carbonyl halide of the general formula (II) is either added in liquid form without using a solvent or as a solution in a solvent which is inert under the reaction conditions.
- solvents include toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, anisole, cyclohexane, methylcyclohexane, pentane, heptane, isooctane or mixtures of these solvents.
- Use is preferably made of toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, anisole, methylcyclohexane, heptane, isooctane or mixtures of these solvents. Use is particularly preferably made of toluene.
- aqueous base solution is metered in simultaneously to the metering in of the carbonyl halide of the general formula (III).
- equimolar amounts of base are metered in in parallel to the carbonyl halide, or the reaction is carried out under pH control and the metering in of the base is adapted accordingly.
- the first step (1) of the process according to the invention is for example carried out at a temperature of between 0 and 100° C.; preferably between 10 and 70° C.
- the N-acylated amino acid salts of the general formula (IV) may be isolated or the aqueous solutions of the N-acylated amino acid salts of the general formula (IV) are used without work-up in the second step of the inventive process. Preference is given to using the aqueous solutions without further work-up.
- N-acylated amino acid salts of the general formula (IV) may for example be carried out by concentrating the aqueous solutions under reduced pressure.
- One method of the inventive process for isolating the N-acylated amino acid salts of the general formula (IV) consists of increasing the cation concentration (sodium or potassium) in the solution by addition of, for example, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium chloride, sodium sulfate, potassium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium chloride or potassium sulfate.
- sodium hydroxide sodium carbonate, sodium hydrogencarbonate, sodium chloride, sodium sulfate, potassium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium chloride or potassium sulfate.
- the N-acylated amino acid salts of the general formula (IV) are reacted with an alkylating agent of the general formula (V) or (VI) to give the amino acid esters of the general formula (I).
- an alkylating agent of the general formula (V) or (VI) Preference is given to using dimethyl sulfate as alkylating agent.
- the alkylating agent is used in amounts from 1 to 5 molar equivalents, based on the N-acylated amino acid salt of the general formula (IV). Preference is given to using 1.5 to 2.5 molar equivalents.
- the pH of the reaction mixture is kept at between 8 to 14, preferably at between 8 to 12.5, by the simultaneous addition of a base.
- useful bases include lithium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide or mixtures of these bases.
- Use is preferably made of sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide or mixtures of these bases.
- the reaction temperature in the second step (2) of the inventive process can be varied within wide limits. On the one hand, the reaction temperature will be chosen to be as high as possible in order to achieve a rapid and complete reaction. On the other hand, the reaction temperature will be chosen to be low enough that, as far as possible, alkaline hydrolysis of the N-acylated amino acid ester of the general formula (I) formed does not occur. Accordingly, the reaction temperature also depends on the pH chosen in the second step (2) of the inventive process. It is typically between 0 and 120° C., preferably between 15 and 90° C.
- the second step (2) of the inventive process may be carried out either without, or in the presence of, a phase transfer catalyst.
- the reaction is preferably carried out with the use of a phase transfer catalyst.
- the amount of phase transfer catalyst is typically between 0.01 and 0.2 molar equivalents, preferably between 0.08 and 0.12 molar equivalents.
- phase transfer catalysts tri-n-butyl-n-tetradecylphosphonium chloride, tetraphenylphosphonium bromide, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetraoctylammonium chloride or tetradecylammonium chloride or mixtures of such tetraalkylammonium salts, such as Aliquat336.
- Use is preferably made of tri-n-butyl-n-tetradecylphosphonium chloride, tetraoctylammonium chloride such as Aliquat 336, tetradecylammonium chloride or mixtures of these tetraalkylammonium salts. Use is particularly preferably made of Aliquat 336.
- the second step (2) of the inventive process may also be carried out at reduced or also increased pressure.
- the selection of the work-up methods is determined by the properties of the amino acid ester prepared.
- Example 1 sodium 8- [2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate
- a solution of 47.3 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 70.8% (corresponding to 150 mmol; the remainder is essentially sodium carbonate and sodium hydroxide) in 108 ml of water is initially charged in a 600 ml reaction vessel with overhead stirrer, pH electrode and metering unit.
- the pH of the slightly cloudy solution is 12.9.
- the mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid.
- HPLC analysis shows a proportion of 75.4% of 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (alongside 24.0% 4-chloro-2,6-dimethylphenylacetic acid and 0.1% toluene).
- a solution of 18.92 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 70.8% (corresponding to 60 mmol; the remainder is essentially sodium carbonate and sodium hydroxide) in 43 ml of water is initially charged in a 100 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 14.33 g [66 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 7.5 ml of toluene is subsequently metered in within one hour.
- a second third of the aqueous phase has 9.1 g of 32% sodium hydroxide solution added to it at 50° C., as a result of which a solid precipitates out. Stirring is carried out at 50° C. for 15 minutes, the mixture is allowed to cool to room temperature, and stirring is carried out for a further 30 minutes. The solid is filtered off and dried. This gives 9.1 g of yellowish solid, which, according to quantitative NMR analysis, consists of 67.8% of the title compound, corresponding to a yield of 76.5% of theory (scaled up to the whole batch).
- a solution of 18.84 g of potassium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 76.2% (corresponding to 60 mmol; the remainder is essentially potassium carbonate and potassium hydroxide) in 43 ml of water is initially charged in a 100 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 14.33 g [66 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 6.5 ml of toluene is subsequently metered in within one hour.
- a solution of 159.5 g [0.600 mol] of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 80.4% (the remainder is essentially sodium carbonate and sodium hydroxide) in 441.8 ml of water is initially charged in a 1000 ml reaction vessel with overhead stirrer, pH electrode and metering unit.
- the pH of the slightly cloudy solution is 13.3.
- the mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 8.2 g of 31% hydrochloric acid.
- a solution of 130.0 g [0.599 mol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 113.4 g of toluene is subsequently metered in within two and a half hours.
- 86.9 g [0.695 mol NaOH] of 32% sodium hydroxide solution is metered in such that the pH remains constant at 11.8.
- stirring is carried out for a further hour at 10° C. and during this the pH is kept at 11.8 by further addition of 32% sodium hydroxide solution.
- the reaction mixture is heated to 20° C.
- the reaction mixture has 146.1 g of toluene added thereto, in order to be able to better disperse the solid forming.
- the solid is filtered off and successively washed with 300 g of water and three times with in each case 150 g of toluene. After drying the solid, this gives 214.3 g [0.482 mol] of the desired product with a purity of 89.1% (HPLC, external standard). This corresponds to a yield of 80%.
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Abstract
The present invention relates to a novel process for the esterification of N-acylated amino acids which contain an acid-labile keto protective group under alkaline conditions without using a polar aprotic solvent, in which the N-acylated amino acid with acid-labile keto protective group prepared in situ is esterified using an alkyl halide or a mono- or dialkyl ester of sulfuric acid.
Description
- This application is a continuation of U.S. patent application Ser. No. 17/047,994, filed 15 Oct. 2020, which is the National Stage entry of International Application No. PCT/EP2019/059641, filed 15 Apr. 2019, which claims priority to European Patent Application No. 18167708.9, filed 17 Apr. 2018. Each of these applications is incorporated by reference in its entirety
- The present invention relates to a novel process for preparing esters of N-acylated amino acids from N-acylated amino acids which contain an acid-labile keto protective group and readily available organic alkylating reagents. The esters of N-acylated amino acids serve as precursors for the preparation of crop protection compositions with insecticidal, acaricidal or herbicidal action (for example WO 06/089633).
- It is already known that amino acids react with alcohols in the presence of hydrogen chloride to give the corresponding amino acid esters (Houben-Weyl, XI/2, S. 355 ff). However, this general preparation method fails when the amino acids contain acid-labile protective groups which are cleaved off under these reaction conditions.
- In such cases, the already known method is applied according to which amino acids are esterified in a polar aprotic solvent using an alkylating reagent in the presence of a base. Thus, e.g., Dhavale et al. (RSC Advances 5, 81165 (2015)) use methyl iodide as alkylating reagent, potassium hydrogencarbonate as base and N,N-dimethylformamide (DMF) as solvent for the preparation of the methyl ester of (1,2-O-isopropylidene-3-O-tosyl-5-deoxy-5-C(S)-(2(5-oxopyrolidine))-α-D-glucohexofurano)uronic acid. According to WO 02/055481 and US005770732, the use of potassium carbonate instead of potassium hydrogencarbonate is also customary. Meienhofer et al. (J. Org. Chem. 42, 1286 (1977)) describe the use of the highly expensive caesium carbonate as base.
- The examples from the literature show that the application of these esterification methods is restricted to the use of a polar aprotic solvent and a weak base. However, the use of typical polar aprotic solvents such as DMF or N,N-dimethylacetamide (DMAC) has the drawback that these solvents can commonly only be recovered using expensive methods, and yet because of their relatively high price, such recovery is however desirable for economic reasons.
- It is also already known to use potassium hydroxide, which is a stronger base in comparison to potassium hydrogencarbonate and potassium carbonate. In this case, however, according to Creighton et al. (J. Am. Chem. Soc. 121, 6786 (1999)), not only the oxygen of the carboxyl group but also the nitrogen of the amino acid, protected here by a tert-butyloxycarbonyl (Boc) group, is alkylated.
- Furthermore, the methods for esterification of carboxylic acids with diazoalkane described in textbooks of organic chemistry (e.g. J. March, Advanced organic chemistry, 3rd edition, John Wiley & Sons 1985, p. 354, ISBN 0-471-85472-7) can be applied to amino acids, as is known inter alia from US20100120727. Yet, for safety-related and economical reasons, diazoalkanes are essentially only used in the laboratory, and are hardly considered for large-scale technical use.
- There was accordingly still a need to provide a more widely applicable, safer and economical technical process for preparing esters of N-acylated amino acids bearing acid-labile keto protective groups.
- Surprisingly, it has now been found that the esterification of N-acylated amino acids which contain an acid-labile keto protective group under alkaline conditions is possible without using a polar aprotic solvent, by the N-acylated amino acid with acid-labile keto protective group prepared in situ being esterified using an alkyl halide or a mono- or dialkyl ester of sulfuric acid.
- Thus, the present invention provides a novel process for preparing compounds of the general formula (I)
- in which
-
- R1 is straight-chain or branched C1-C6 alkyl or benzyl,
- R2 is straight-chain or branched C1-C6 alkyl or phenyl optionally substituted by methyl, ethyl, fluorine, chlorine, methoxy or ethoxy,
- R3 and R4 independently of one another are an OR5 or SR5 radical or together are an —O(CHR6)nO— radical or together are an ═NR7 radical,
wherein - R5 is straight-chain or branched C1-C6 alkyl,
- n is 2 or 3,
- R7 is straight-chain or branched C1-C6 alkyl, phenyl, benzyl or 4-methoxybenzyl, characterized in that in a first step (1) amino acid salts of the general formula (II)
- in which
-
- M is sodium, potassium or an NR84 group,
wherein - R8 is hydrogen or straight-chain or branched C1-C6 alkyl
and - R3 and R4 have the definition given above,
- are reacted with carbonyl halides of the general formula (III)
- M is sodium, potassium or an NR84 group,
- in which
-
- Y is fluorine, chlorine or bromine, and
- R2 has the meaning given above,
to give N-acylated amino acid salts of the general formula (IV)
- in which
-
- M, R2, R3 and R4 have the definitions given above,
in the presence of a base and a solvent or solvent mixture, which is not polar aprotic, and subsequent thereto in a second step (2) of the inventive process, the N-acylated amino acids of the general formula (IV) are reacted with an alkylating reagent of the general formula (V) or (VI) in the presence of a base and a solvent or solvent mixture, which is not polar aprotic, to give the compounds of the general formula (I).
- M, R2, R3 and R4 have the definitions given above,
- As alkylating reagents, use may be made of alkyl halides of the general formula (V) or sulfuric acid di- or monoesters or salts of the sulfuric acid monoester of the general formula (VI)
- in which
-
- R1 has the definition given above,
- Z is chlorine, bromine or iodine
and - R9 is hydrogen, sodium, potassium or the radical R1.
- The compounds of the formula (II) and (III) are either commercially available or can be prepared by known processes.
- The compounds of the formulae (V) and (VI) are commercially available.
- The inventive process is depicted by Scheme 1.
- Preference is given to the process for preparing compounds of the general formula (I),
- wherein
-
- R1 is methyl, ethyl, n-propyl, n-butyl or benzyl,
- R2 is phenyl, optionally substituted by methyl, ethyl, chlorine, methoxy or ethoxy,
- R3 and R4 independently of one another are an OR5 radical or together are an —O(CHR6)nO— radical or together are an ═NR7 radical,
- R5 is straight-chain C1-C6-alkyl,
- R6 is hydrogen, methyl, ethyl or phenyl,
- n is 2 or 3,
- R7 is straight-chain or branched C1-C6 alkyl, phenyl, benzyl or 4-methoxybenzyl,
- M is sodium or potassium,
- Y is fluorine or chlorine,
-
- Z is chlorine, bromine or iodine,
- R9 is hydrogen, sodium, potassium or the radical R1.
- Particular preference is given to the process for preparing compounds of the general formula (I),
- wherein
-
- R1 is methyl, ethyl, n-propyl or n-butyl,
- R2 is phenyl, optionally substituted by methyl, ethyl or chlorine,
- R3 and R4 are an OR5 radical or together are an —O(CH2)2O— radical,
- R5 is methyl, ethyl, n-propyl or n-butyl,
- M is sodium or potassium,
- Y is chlorine,
- Z is bromine or iodine,
- R9 is hydrogen, sodium, potassium or the radical R1.
- Emphasis is given to the process for preparing the compound of the formula (I-1,)
- characterized in that in a first step (1) the amino acid salt of the general formula (II-1)
- in which
-
- M is sodium or potassium,
is reacted with the carbonyl halide of the formula (III-1)
- M is sodium or potassium,
- to give N-acylated amino acid salts of the general formula (IV-1)
- in which
-
- M is sodium or potassium,
in the presence of a base and a solvent or solvent mixture, which is not polar aprotic, and subsequent thereto in a second step (2) of the inventive process, the N-acylated amino acids of the general formula (IV-1) are reacted with dimethyl sulfate (compound of the formula (VI-1), in which R1 and R9 are methyl) in the presence of a base and a solvent or solvent mixture, which is not polar aprotic, to give the compound of the formula (I-1).
- M is sodium or potassium,
- The present invention likewise provides novel compounds of the general formula (I-a)
- in which
-
- R1 is methyl, ethyl, n-propyl, n-butyl or benzyl,
and - R3 and R4 are an ORS radical or together are an —O(CH2)2O— radical,
wherein - R5 is methyl, ethyl, n-propyl or n-butyl,
wherein, if R1 is methyl, then R5 is not methyl,
wherein, if R1 is methyl, then R3 and R4 are not together a radical —O(CH2)2O—.
- R1 is methyl, ethyl, n-propyl, n-butyl or benzyl,
- Preference is given to novel compounds of the general formula (I-a), in which
-
- R1 is ethyl, n-propyl or n-butyl,
and - R3 and R4 are together an —O(CH2)2O— radical.
- R1 is ethyl, n-propyl or n-butyl,
- The present invention likewise provides novel compounds of the general formula (IV-1)
- in which
-
- M is sodium or potassium.
- There follows a detailed elucidation of the process according to the invention:
- Specifically, the inventive process will be carried out such that, in the first step (1), firstly amino acid salts of the general formula (II) are dissolved in water or an aqueous solution of a base or these amino acid salts of the general formula (II) are produced by the corresponding free amino acids or salts of the amino acids being dissolved with acids such as hydrochlorides, sulfates or hydrosulfates in an aqueous solution of a base.
- Examples of useful bases include lithium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide or mixtures of these bases. Use is preferably made of sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide or mixtures of these bases.
- The amount of base is selected such that a pH of 8 to 14 is established. Preferably, a pH of 10.5 to 12.5 is established.
- It may optionally be necessary to adjust the pH to the desired range by subsequent addition of an inorganic acid. Useful inorganic acids include hydrochloric acid or sulfuric acid, preferably hydrochloric acid.
- Subsequently, in this first step (1) of the inventive process, the aqueous solution of the amino acid salts of the general formula (II) is reacted with a carbonyl halide of the general formula (III) to give an N-acylated amino acid salt of the general formula (IV).
- The amount of carbonyl halide of the general formula (III) in this case is 0.9 to 1.5 molar equivalents, based on the amino acid salt of the general formula (II). Preference is given to using 1.0 to 1.25 molar equivalents.
- The carbonyl halide of the general formula (II) is either added in liquid form without using a solvent or as a solution in a solvent which is inert under the reaction conditions. Examples of useful solvents include toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, anisole, cyclohexane, methylcyclohexane, pentane, heptane, isooctane or mixtures of these solvents. Use is preferably made of toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, anisole, methylcyclohexane, heptane, isooctane or mixtures of these solvents. Use is particularly preferably made of toluene.
- If required in order to maintain the desired pH, further aqueous base solution is metered in simultaneously to the metering in of the carbonyl halide of the general formula (III). In this case, either equimolar amounts of base are metered in in parallel to the carbonyl halide, or the reaction is carried out under pH control and the metering in of the base is adapted accordingly.
- The first step (1) of the process according to the invention is for example carried out at a temperature of between 0 and 100° C.; preferably between 10 and 70° C.
- The N-acylated amino acid salts of the general formula (IV) may be isolated or the aqueous solutions of the N-acylated amino acid salts of the general formula (IV) are used without work-up in the second step of the inventive process. Preference is given to using the aqueous solutions without further work-up.
- If it is intended to isolate the N-acylated amino acid salts of the general formula (IV), this may for example be carried out by concentrating the aqueous solutions under reduced pressure. One method of the inventive process for isolating the N-acylated amino acid salts of the general formula (IV) consists of increasing the cation concentration (sodium or potassium) in the solution by addition of, for example, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium chloride, sodium sulfate, potassium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium chloride or potassium sulfate. As a result, this leads either to the formation of a second aqueous phase which contains the N-acylated amino acid salt, or the N-acylated amino acid salt precipitates out and can be filtered off.
- In the second step (2) of the inventive process, the N-acylated amino acid salts of the general formula (IV) are reacted with an alkylating agent of the general formula (V) or (VI) to give the amino acid esters of the general formula (I). Preference is given to using dimethyl sulfate as alkylating agent.
- The alkylating agent is used in amounts from 1 to 5 molar equivalents, based on the N-acylated amino acid salt of the general formula (IV). Preference is given to using 1.5 to 2.5 molar equivalents.
- During the metering in of the alkylating agent of the general formula (V) or (VI), the pH of the reaction mixture is kept at between 8 to 14, preferably at between 8 to 12.5, by the simultaneous addition of a base.
- Examples of useful bases include lithium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide or mixtures of these bases. Use is preferably made of sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide or mixtures of these bases.
- The reaction temperature in the second step (2) of the inventive process can be varied within wide limits. On the one hand, the reaction temperature will be chosen to be as high as possible in order to achieve a rapid and complete reaction. On the other hand, the reaction temperature will be chosen to be low enough that, as far as possible, alkaline hydrolysis of the N-acylated amino acid ester of the general formula (I) formed does not occur. Accordingly, the reaction temperature also depends on the pH chosen in the second step (2) of the inventive process. It is typically between 0 and 120° C., preferably between 15 and 90° C.
- The second step (2) of the inventive process may be carried out either without, or in the presence of, a phase transfer catalyst. The reaction is preferably carried out with the use of a phase transfer catalyst.
- The amount of phase transfer catalyst is typically between 0.01 and 0.2 molar equivalents, preferably between 0.08 and 0.12 molar equivalents.
- The following may be mentioned as examples of typical phase transfer catalysts: tri-n-butyl-n-tetradecylphosphonium chloride, tetraphenylphosphonium bromide, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetraoctylammonium chloride or tetradecylammonium chloride or mixtures of such tetraalkylammonium salts, such as Aliquat336.
- Use is preferably made of tri-n-butyl-n-tetradecylphosphonium chloride, tetraoctylammonium chloride such as Aliquat 336, tetradecylammonium chloride or mixtures of these tetraalkylammonium salts. Use is particularly preferably made of Aliquat 336.
- The second step (2) of the inventive process, as well as being carried out at normal pressure, may also be carried out at reduced or also increased pressure.
- The selection of the work-up methods is determined by the properties of the amino acid ester prepared.
- The present invention is illustrated in more detail by the examples which follow without being restricted thereby.
-
- A solution of 47.3 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 70.8% (corresponding to 150 mmol; the remainder is essentially sodium carbonate and sodium hydroxide) in 108 ml of water is initially charged in a 600 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The pH of the slightly cloudy solution is 12.9. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 36.5 g [168 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 23 ml of toluene is subsequently metered in within one hour. At the same time, 25.1 g of 32% sodium hydroxide solution [201 mmol NaOH] is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C., the mixture is allowed to return to room temperature, and the phases are separated. This gives 220 g of a cloudy yellow solution, which can be used in the next step without further work-up. HPLC analysis (acid) shows a proportion of 75.4% of 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (alongside 24.0% 4-chloro-2,6-dimethylphenylacetic acid and 0.1% toluene).
-
- A solution of 18.92 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 70.8% (corresponding to 60 mmol; the remainder is essentially sodium carbonate and sodium hydroxide) in 43 ml of water is initially charged in a 100 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 14.33 g [66 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 7.5 ml of toluene is subsequently metered in within one hour. At the same time, 23.6 g of 32% sodium hydroxide solution [188 mmol NaOH] is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C., the mixture is allowed to return to room temperature, and the phases are separated. A third of the aqueous phase has 9.1 g of 32% sodium hydroxide solution added to it at room temperature, as a result of which a solid precipitates out. This solid is filtered off and dried. This gives 1.8 g of yellowish solid, which, according to 1 H NMR analysis, consists of 69.2% of the title compound.
- HPLC analysis (acid): 82.6% 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro [4.5]decane-8-carboxylic acid (alongside 14.1% 4-chloro-2,6-dimethylphenylacetic acid).
- Ion chromatography: 7.26% sodium (theoretical value: 5.7%)
- 1H NMR (600 MHz, D2O): δ=1.6-1.7 (m; 2H). 1.73-1.8 (m; 2H), 1.9-2 (m;2H), 2.05 -2.13 (m; 2H), 2.3 (s; 6H), 3.7 (s; 2H), 4.03 (s; 4H), 7.12 (s; 2H) ppm.
- More solid precipitates from the filtrate. After drying, this gives 3.4 g of solid, which, according to 1H NMR analysis, consists of 67.3% of the title compound.
- Both solid fractions add up to a yield of 44% of theory (scaled up to the whole batch).
- A second third of the aqueous phase has 9.1 g of 32% sodium hydroxide solution added to it at 50° C., as a result of which a solid precipitates out. Stirring is carried out at 50° C. for 15 minutes, the mixture is allowed to cool to room temperature, and stirring is carried out for a further 30 minutes. The solid is filtered off and dried. This gives 9.1 g of yellowish solid, which, according to quantitative NMR analysis, consists of 67.8% of the title compound, corresponding to a yield of 76.5% of theory (scaled up to the whole batch).
-
- A solution of 18.84 g of potassium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 76.2% (corresponding to 60 mmol; the remainder is essentially potassium carbonate and potassium hydroxide) in 43 ml of water is initially charged in a 100 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 10% hydrochloric acid. A solution of 14.33 g [66 mmol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 6.5 ml of toluene is subsequently metered in within one hour. At the same time, 22.9 g of 45% potassium hydroxide solution [184 mmol KOH] is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C., the mixture is allowed to return to room temperature, and the phases are separated. Half of the aqueous phase has 13.7 g of 45% potassium hydroxide solution added thereto, as a result of which two phases form. The phases are separated and the lower phase (24.7 g) is concentrated under reduced pressure. This gives 15.7 g of yellowish solid, which, according to quantitative NMR analysis, consists of 67.7% of the title compound, corresponding to a yield of 84.4% of theory (scaled up to the whole batch). HPLC analysis (acid): 77.9% 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (alongside 12.4% 4-chloro-2,6-dimethylphenylacetic acid and 9.3% toluene). Ion chromatography: 11.6% potassium (theoretical value: 9.3%).
- 1H NMR (600 MHz, D2O): δ=1.5-1.6 (m; 2H). 1.65-1.7 (m; 2H), 1.8-1.9 (m;2H), 1.95 -2 (m; 2H), 2.22 (s; 6H), 3.67 (s; 2H), 4 (s; 4H), 7.09 (s; 2H) ppm.
-
- 310.0 g [0.486 mol] of a 16.6% solution of sodium carbonate in water, 15.4 g of water and 110.4 g [0.371 mol] of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate with a purity of 75.0% (the remainder is essentially sodium carbonate and sodium hydroxide) are initially charged at room temperature into a 1000 ml reaction vessel with overhead stirrer, pH electrode, baffle and metering unit. The pH of the suspension is 13.9. The pH is adjusted to 11.8 at 20° C. by addition of 37.8 g of an 18.8% hydrochloric acid. A solution of 88.8 g [0.409 mol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 67.6 g of toluene is subsequently metered in within three and a half hours. After the metering in has been completed, stirring is carried out for a further hour at 20° C., 166.1 g of toluene are added thereto, and the reaction mixture is heated to 80° C. At 80° C., 3.1 g [0.007 mol, purity 99%] of methyl tri-n-octylammonium chloride (Aliquat 336) are added thereto and 136.1 g [1.074 mol, purity 99.5%] of dimethyl sulfate are subsequently metered in in two hours. Before cooling to 20° C., the mixture is stirred for a further hour at 80° C. The product that precipitated out during the dimethyl sulfate metering is subsequently filtered off and the filter cake is washed twice with in each case 458 g of water and twice with in each case 176 g of toluene. After drying, this gives 115.6 g [0.285 mol] of methyl-8[2-(4-chloro-2,6-dimethylphenyl)acetamidol]-1,4-dioxaspiro[4.5]decane-8-carboxylate with a purity of 97.6% (HPLC, external standard). This corresponds to a yield of 77%.
-
- A solution of 159.5 g [0.600 mol] of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate of a purity of 80.4% (the remainder is essentially sodium carbonate and sodium hydroxide) in 441.8 ml of water is initially charged in a 1000 ml reaction vessel with overhead stirrer, pH electrode and metering unit. The pH of the slightly cloudy solution is 13.3. The mixture is cooled to 10° C. and the pH is adjusted to 11.8 by addition of 8.2 g of 31% hydrochloric acid. A solution of 130.0 g [0.599 mol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 113.4 g of toluene is subsequently metered in within two and a half hours. At the same time, 86.9 g [0.695 mol NaOH] of 32% sodium hydroxide solution is metered in such that the pH remains constant at 11.8. After the metering in has been completed, stirring is carried out for a further hour at 10° C. and during this the pH is kept at 11.8 by further addition of 32% sodium hydroxide solution. The reaction mixture is heated to 20° C. At 20° C., 24.6 g [0.060 mol, purity 99%] of methyl-tri-n-octylammonium chloride are added thereto, and 153.0 g of dimethyl sulfate [1.201 mol, purity 99.0%] are metered in in one and a half hours. In parallel to the dimethyl sulfate metering, 23.0 g [0.184 mol NaOH] of 32% sodium hydroxide solution is metered in such that the pH remains constant at 11.8. The reaction mixture is stirred for a further hour and a half at 20° C. and during this the pH is kept at 11.8 by further addition of 32% sodium hydroxide solution. In the phase of further stirring, the reaction mixture has 146.1 g of toluene added thereto, in order to be able to better disperse the solid forming. At the end of the further stirring period, the solid is filtered off and successively washed with 300 g of water and three times with in each case 150 g of toluene. After drying the solid, this gives 214.3 g [0.482 mol] of the desired product with a purity of 89.1% (HPLC, external standard). This corresponds to a yield of 80%.
- Example 6: 11-(4-Chloro-2,6-dimethylphenyl)-12-hydroxy-1,4-dioxa-9-azadispiro[4.2.48.25]tetradec-11-en-10-one
- 4.9 g [12.37 mmol] of methyl-8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate in 20 ml of anhydrous N,N-dimethylformamide are initially charged and 5.57 g [30.9 mmol] of a 30% solution of NaOMe in methanol are then added thereto. The reaction mixture is heated for three hours at 80° C. and the methanol is distilled off. Stirring is subsequently carried out for a further 16 hours at 110° C. The reaction mixture is stirred in at room temperature to a mixture of 100 ml of water and 25 ml of glacial acetic acid. The precipitated solid is filtered off with suction, washed twice with water and dried. This gives 4.4 g of a light beige solid with a purity of 97.3% according to HPLC analysis. This corresponds to a yield of 95% of theory.
Claims (7)
1. A compound of formula (I-a)
wherein
R1 is methyl, ethyl, n-propyl, n-butyl or benzyl,
and
R3 and R4 are an OR5 radical or together are an —O(CH2)2O— radical,
wherein
R5 is methyl, ethyl, n-propyl or n-butyl,
wherein, if R1 is methyl, then R5 is not methyl,
wherein, if R1 is methyl, then R3 and R4 are not together a radical —O(CH2)2O—.
2. The compound of formula (I-a) according to claim 1 , wherein
R1 is ethyl, n-propyl or n-butyl,
and
R3 and R4 are together an —O(CH2)2O— radical.
3. The compound of formula (I-a) according to claim 1 , wherein
wherein, if R1 is methyl, then R5 is not methyl, and
wherein, if R1 is methyl or ethyl, then R3 and R4 are not together a radical —O(CH2)2O—.
4. The compound of formula (I-a) according to claim 1 , wherein
R1 is n-propyl, n-butyl or benzyl.
5. The compound of formula (I-a) according to claim 2 , wherein
R1 is n-propyl or n-butyl.
7. A process for isolating a compound of formula (IV),
wherein
M is sodium, potassium or an NR8 4 group,
R1 is straight-chain or branched C1-C6 alkyl or benzyl,
R2 is straight-chain or branched C1-C6 alkyl or phenyl optionally substituted by methyl, ethyl, fluorine, chlorine, methoxy or ethoxy,
R3 and R4 independently of one another are an OR5 or SR5 radical or together are an —O(CH2)2O— radical or together are an ═NR7 radical,
wherein
R5 is straight-chain or branched C1-C6 alkyl,
R6 is hydrogen, methyl, ethyl or phenyl,
n is 2 or 3,
R7 is straight-chain or branched C1-C6 alkyl, phenyl, benzyl or 4-methoxybenzyl,
R8 is hydrogen or straight-chain or branched C1-C6 alkyl,
wherein the cation concentration (sodium or potassium) in a solution is increased by addition of sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium chloride, sodium sulfate, potassium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium chloride or potassium sulfate and as a result either forming a second aqueous phase which contains the compound of formula (IV), or the compound of formula (IV) precipitates out and is filtered off.
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US202017047994A | 2020-10-15 | 2020-10-15 | |
US17/743,534 US20220267291A1 (en) | 2018-04-17 | 2022-05-13 | Process for preparing esters of n-acylated amino acids with acid-labile keto protective group functions |
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US17/047,994 Continuation US11384061B2 (en) | 2018-04-17 | 2019-04-15 | Process for preparing esters of N-acylated amino acids with acid-labile keto protective group functions |
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US7897543B2 (en) * | 2005-02-22 | 2011-03-01 | Bayer Cropscience Ag | Spiroketal-substituted cyclic ketoenols |
WO2018024659A1 (en) * | 2016-08-04 | 2018-02-08 | Bayer Cropscience Aktiengesellschaft | Method for producing spiroketal-substituted cyclic ketoenols |
EP3301092A2 (en) * | 2018-01-26 | 2018-04-04 | Bayer CropScience Aktiengesellschaft | Process for the production of spiroketal-substituted phenylacetylamino acid esters and spiroketal-substituted cyclic ketoenols |
US20210032262A1 (en) * | 2018-04-10 | 2021-02-04 | Bayer Aktiengesellschaft | Process for preparing substituted cyclohexane amino acid esters and spiroketal-substituted cyclic keto-enols |
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US5770732A (en) | 1993-02-17 | 1998-06-23 | The Trustees Of The University Of Pennsylvania | Pyrrolinone-based peptidomimetics |
DE19742492A1 (en) | 1997-09-26 | 1999-04-01 | Bayer Ag | Spirocyclic phenylketoenols |
NZ526050A (en) * | 2001-01-11 | 2005-03-24 | Lilly Co Eli | Prodrugs of excitatory amino acids |
WO2010056919A2 (en) | 2008-11-12 | 2010-05-20 | Kyphia Pharmaceuticals, Inc. | Eflornithine prodrugs, conjugates and salts, and methods of use thereof |
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US7897543B2 (en) * | 2005-02-22 | 2011-03-01 | Bayer Cropscience Ag | Spiroketal-substituted cyclic ketoenols |
WO2018024659A1 (en) * | 2016-08-04 | 2018-02-08 | Bayer Cropscience Aktiengesellschaft | Method for producing spiroketal-substituted cyclic ketoenols |
US20190202837A1 (en) * | 2016-08-04 | 2019-07-04 | Bayer Cropscience Aktiengesellschaft | Process for preparing spiroketal-substituted cyclic ketoenols |
EP3301092A2 (en) * | 2018-01-26 | 2018-04-04 | Bayer CropScience Aktiengesellschaft | Process for the production of spiroketal-substituted phenylacetylamino acid esters and spiroketal-substituted cyclic ketoenols |
US20210032262A1 (en) * | 2018-04-10 | 2021-02-04 | Bayer Aktiengesellschaft | Process for preparing substituted cyclohexane amino acid esters and spiroketal-substituted cyclic keto-enols |
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US20210139450A1 (en) | 2021-05-13 |
TWI809089B (en) | 2023-07-21 |
CN112041310B (en) | 2023-11-03 |
KR20200143392A (en) | 2020-12-23 |
WO2019201842A1 (en) | 2019-10-24 |
IL277967B2 (en) | 2023-10-01 |
JP7349449B2 (en) | 2023-09-22 |
JP2021521221A (en) | 2021-08-26 |
EP3781552A1 (en) | 2021-02-24 |
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