DK3066071T3 - Fremgangsmåde til fremstilling af iopamidol - Google Patents
Fremgangsmåde til fremstilling af iopamidol Download PDFInfo
- Publication number
- DK3066071T3 DK3066071T3 DK14796024.9T DK14796024T DK3066071T3 DK 3066071 T3 DK3066071 T3 DK 3066071T3 DK 14796024 T DK14796024 T DK 14796024T DK 3066071 T3 DK3066071 T3 DK 3066071T3
- Authority
- DK
- Denmark
- Prior art keywords
- compound
- group
- butyl
- formula
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 92
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 title claims description 16
- 229960004647 iopamidol Drugs 0.000 title claims 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 65
- 230000008569 process Effects 0.000 claims abstract description 59
- 229910052796 boron Inorganic materials 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 31
- 238000011084 recovery Methods 0.000 claims abstract description 31
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 29
- -1 (S)-2-(hydroxy)propanoyl group Chemical group 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 25
- ALHZEIINTQJLOT-VKHMYHEASA-N [(2s)-1-chloro-1-oxopropan-2-yl] acetate Chemical compound ClC(=O)[C@H](C)OC(C)=O ALHZEIINTQJLOT-VKHMYHEASA-N 0.000 claims abstract description 22
- 125000006239 protecting group Chemical group 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 19
- 239000012429 reaction media Substances 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 11
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims abstract description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 7
- 239000012670 alkaline solution Substances 0.000 claims abstract description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract 4
- 238000006243 chemical reaction Methods 0.000 claims description 50
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 50
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 39
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 37
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 37
- 230000015572 biosynthetic process Effects 0.000 claims description 37
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 36
- 239000004327 boric acid Substances 0.000 claims description 35
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 32
- 238000003786 synthesis reaction Methods 0.000 claims description 28
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 24
- BRTALTYTFFNPAC-UHFFFAOYSA-N boroxin Chemical compound B1OBOBO1 BRTALTYTFFNPAC-UHFFFAOYSA-N 0.000 claims description 20
- 239000006184 cosolvent Substances 0.000 claims description 20
- 230000007062 hydrolysis Effects 0.000 claims description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- NBDAHKQJXVLAID-UHFFFAOYSA-N 5-nitroisophthalic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC([N+]([O-])=O)=C1 NBDAHKQJXVLAID-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000005690 diesters Chemical class 0.000 claims description 12
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 12
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 claims description 12
- FFWSICBKRCICMR-UHFFFAOYSA-N 5-methyl-2-hexanone Chemical compound CC(C)CCC(C)=O FFWSICBKRCICMR-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 238000006192 iodination reaction Methods 0.000 claims description 10
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 claims description 9
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 230000026045 iodination Effects 0.000 claims description 8
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 7
- QPKFVRWIISEVCW-UHFFFAOYSA-N 1-butane boronic acid Chemical compound CCCCB(O)O QPKFVRWIISEVCW-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims description 5
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 5
- 238000000638 solvent extraction Methods 0.000 claims description 5
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 claims description 4
- VOXXGUAZBWSUSS-UHFFFAOYSA-N 2,4,6-triphenyl-1,3,5,2,4,6-trioxatriborinane Chemical compound O1B(C=2C=CC=CC=2)OB(C=2C=CC=CC=2)OB1C1=CC=CC=C1 VOXXGUAZBWSUSS-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- MBHINSULENHCMF-UHFFFAOYSA-N n,n-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 0.000 claims description 2
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 2
- LTEHWCSSIHAVOQ-UHFFFAOYSA-N tripropyl borate Chemical compound CCCOB(OCCC)OCCC LTEHWCSSIHAVOQ-UHFFFAOYSA-N 0.000 claims description 2
- FVLWRKHQMFPOQE-UHFFFAOYSA-N 5-amino-1-n,3-n-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I FVLWRKHQMFPOQE-UHFFFAOYSA-N 0.000 claims 7
- NSJVYHOPHZMZPN-UHFFFAOYSA-N (2-methylphenyl)boronic acid Chemical compound CC1=CC=CC=C1B(O)O NSJVYHOPHZMZPN-UHFFFAOYSA-N 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- FNWMEZLAQHOBOS-UHFFFAOYSA-N 5-amino-1-n,3-n-bis(1,3-dihydroxypropan-2-yl)benzene-1,3-dicarboxamide Chemical compound NC1=CC(C(=O)NC(CO)CO)=CC(C(=O)NC(CO)CO)=C1 FNWMEZLAQHOBOS-UHFFFAOYSA-N 0.000 claims 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 66
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 abstract description 15
- 238000005580 one pot reaction Methods 0.000 abstract description 11
- 238000002955 isolation Methods 0.000 abstract description 8
- 150000001638 boron Chemical class 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 3
- 230000003247 decreasing effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 37
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- 239000012299 nitrogen atmosphere Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
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- 125000000129 anionic group Chemical group 0.000 description 16
- 239000000725 suspension Substances 0.000 description 15
- 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 14
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- 238000010934 O-alkylation reaction Methods 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- DYXGOCQNHOIWHO-UHFFFAOYSA-N butan-2-ol hydrate Chemical compound O.CCC(C)O DYXGOCQNHOIWHO-UHFFFAOYSA-N 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
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- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- OXIUZVAABWWKMT-UHFFFAOYSA-N ethyl acetate 5-methylhexan-2-one Chemical compound C(C)(=O)OCC.C(CC(C)C)C(=O)C OXIUZVAABWWKMT-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/05—Cyclic compounds having at least one ring containing boron but no carbon in the 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
-
- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Detergent Compositions (AREA)
Claims (22)
- 1. Fremgangsmåde til fremstilling af iopamidol (II), som omfatter følgende reaktion:hvor X er OR2 eller R3, og hvor R2 og R3 er en lineær eller forgrenet Ci-C6-alkyl, C3-C6-cycloalkyl, C6-aryl, der eventuelt er substitueret med en gruppe valgt fra gruppen, der består af methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl og phenyl; og omfatter følgende trin: a) reaktion af forbindelse (I) med acyleringsmidlet (S)—2— (acetyloxy)propanoylchlorid i et reaktionsmedium til tilvejebringelse af N-(S)-2-(acetyloxy)propanoylderivatet af forbindelse (I); b) hydrolyse af mellemproduktet fra trin a) med en vandig opløsning ved et pH fra 0 til 7 ved tilsætning af vand eller en fortyndet alkalisk opløsning, der frigør hydroxylerne fra de borholdige beskyttelsesgrupper til opnåelse af acetyloxyderivatet af forbindelse (II), og eventuelt indvinding af borderivatet; c) alkalisk hydrolyse af acetyloxyderivatet af forbindelse (II), der reetablerer (S)-2-(hydroxy)propanoylgruppen til opnåelse af iopamidol (II) .
- 2. Fremgangsmåde ifølge krav 1, hvor X er OR2.
- 3. Fremgangsmåde ifølge krav 1, hvor X er R3.
- 4. Fremgangsmåde ifølge et hvilket som helst af kravene 1-3, hvor reaktionsmediet i trin a) er et vandfrit, organisk opløsningsmiddel.
- 5. Fremgangsmåde ifølge et hvilket som helst af kravene 1-4,hvor reaktionsmediet i trin a) er valgt fra gruppen, der består af N,N-dimethylformamid, N,N-dimethylacetamid, N,N-diethylacetamid, N,N-dimethylpropionamid, N-methylpyrrolidon, N-ethylpyrrolidon, tetramethylurinstof, N,N'-dimethylethylenurinstof (DMEU) og N,N'-dimethylpropylenurinstof (DMPU), eventuelt blandet med et co-opløsningsmiddel.
- 6. Fremgangsmåde ifølge et hvilket som helst af kravene 1-5, hvor indvinding af borderivatet i trin b) udføres ved hjælp af kromatografi eller ved hjælp af ekstraktion med co-opløsningsmiddel.
- 7. Fremgangsmåde ifølge et hvilket som helst af kravene 1-6, hvor forbindelsen med formel (I) fremstilles startende fra forbindelsen med formel (IV) i henhold til følgende reaktion:hvor X er OR2 eller R3, og hvor R2 og R3 er en lineær eller forgrenet Ci-C6-alkyl, C3-C6-cycloalkyl, C6-aryl, der eventuelt er substitueret med en gruppe valgt fra gruppen, der består af methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl og phenyl; og som omfatter: reaktion af forbindelsen med formel (IV) med den ene af en borsyre i en R20H-alkohol eller en boratester B(OR2)3, hvor R2 er som defineret ovenfor, til tilvejebringelse af forbindelsen med formel (I), hvor X er OR2; eller reaktion af forbindelsen med formel (IV) med den ene af en boronsyre R3-B(OH)2 eller en boroxin med formel (III) :til tilvejebringelse af forbindelsen med formel (I), hvor X er R3.
- 8. Fremgangsmåde ifølge krav 7, hvor der anvendes en boratester B(OR2)3.
- 9. Fremgangsmåde ifølge krav 8, hvor boratesteren er valgt fra gruppen, der består af: tri-n-butylborat, tri-n-propylborat og tri-ethylborat.
- 10. Fremgangsmåde ifølge krav 7, hvor der anvendes en boronsyre R3B(OH)2 eller en boroxin (III).
- 11. Fremgangsmåde ifølge krav 10, hvor boronsyren er valgt fra gruppen, der består af: phenylboronsyre, tolylboronsyre og butylboronsyre, eller boroxinen (III) er valgt fra gruppen, der består af tri-phenylboroxin og tri-methylboroxin.
- 12. Fremgangsmåde ifølge et hvilket som helst af kravene 10 eller 11, som omfatter boronsyreindvinding ved hjælp af ekstraktion med co-opløsningsmiddel, hvor co-opløsningsmidlet er et organisk ikke-vandblandbart opløsningsmiddel valgt fra gruppen, der består af: 4-methyl-2-pentanon, 2-pentanon, 3-pentanon, dibutylether, 2-methyltetrahydrofuran, ciclopentylmethylether, methylisopropylketon, methylisopentylketon, ethylacetat, butylacetat, pentylacetat, isopentylacetat, isopropylacetat.
- 13. Fremgangsmåde ifølge et hvilket som helst af kravene 1-11, som er en én-beholder-fremgangsmåde.
- 14. Fremgangsmåde ifølge krav 7, hvor forbindelsen med formel (IV) fremstilles ved udsættelse af følgende forbindelse (V) for iodering:
- 15. Fremgangsmåde ifølge krav 14, hvor forbindelse (V) fremstilles i henhold til følgende reaktionsskema:hvor :i) 5-nitroisophthalsyre behandles med en RiOH-alkohol, hvor Ri er en lineær eller forgrenet Ci-C4-alkyl, til tilvejebringelse af den tilsvarende diester; ii) 5-nitrogruppen reduceres til den tilsvarende 5-aminogruppe til tilvejebringelse af forbindelse (VII); iii) diesteren reageres med 2-amino-l,3-propandiol til tilvejebringelse af forbindelse (V).
- 16. Fremgangsmåde til fremstilling af iopamidol (II) i henhold til følgende reaktionsskema:hvor: i) 5-nitroisophthalsyre (5-NIPA) behandles med en RiOH-alkohol, hvor Ri er en lineær eller forgrenet Ci-C4alkyl, til tilvejebringelse af diesteren (VI); ii) 5-nitrogruppen reduceres til tilvejebringelse af forbindelse (VII); iii) diesteren reageres med 2-amino-l,3-propandiol til tilvejebringelse af 5-amino-N,N'-bis[2-hydroxy-l- (hydroxymethyl)ethyl]-1,3-benzendicarboxamid (V); iv) forbindelse (V) ioderes i positionerne 2,4,6 til tilvejebringelse af 5-amino-N,N'-bis[2-hydroxy-l- (hydroxymethyl)ethyl]-2,4,6-triiod-l,3-benzendicarboxamid (IV) ; v) forbindelse (IV) behandles med borsyre eller et derivat deraf ifølge et hvilket som helst af kravene 8-12 til tilvejebringelse af forbindelsen med formel (I);vi) forbindelsen med formel (I) transformeres til iopamidol (II) ifølge et hvilket som helst af kravene 1-7 eller 14.
- 17. Fremgangsmåde ifølge et hvilket som helst af kravene 1-16, som yderligere omfatter oprensning og isolering af iopamidol (II).
- 18. Fremgangsmåde ifølge krav 17, hvor oprensningen er til farmaceutisk kvalitet.
- 19. Forbindelse med formel (I)C) hvor X er OR2 eller R3, og hvor R2 og R3 er en lineær eller forgrenet Ci-C6-alkyl, C3-C6-cycloalkyl, C6-aryl, der eventuelt er substitueret med en gruppe valgt fra gruppen, der består af methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl og phenyl.
- 20. Forbindelse ifølge krav 19, hvor X er valgt fra gruppen, der består af: phenyl, methylsubstitueret phenyl, methyl og butyl.
- 21. Forbindelse ifølge krav 20, hvor X er phenyl.
- 22. Anvendelse af forbindelsen med formel (I) ifølge kravene 20-21 og N-(S)-2-(acetyloxy)propanoylderivatet deraf som et mellemprodukt til syntese af iopamidol (II).
Applications Claiming Priority (2)
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| EP13191551 | 2013-11-05 | ||
| PCT/EP2014/073692 WO2015067601A1 (en) | 2013-11-05 | 2014-11-04 | Process for the preparation of iopamidol |
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| EP (2) | EP3369724B1 (da) |
| JP (1) | JP6454351B2 (da) |
| KR (2) | KR102265049B1 (da) |
| CN (1) | CN105705483B (da) |
| AU (1) | AU2014345727B2 (da) |
| BR (1) | BR112016010223B1 (da) |
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| ES (2) | ES2674279T3 (da) |
| HR (2) | HRP20181122T1 (da) |
| HU (2) | HUE039440T2 (da) |
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| PL (2) | PL3369724T3 (da) |
| PT (2) | PT3066071T (da) |
| RU (1) | RU2657238C2 (da) |
| SI (2) | SI3369724T1 (da) |
| TR (1) | TR201808527T4 (da) |
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| ZA (1) | ZA201602970B (da) |
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| CN106366015B (zh) * | 2015-07-22 | 2019-01-25 | 正大天晴药业集团股份有限公司 | 一种碘普罗胺的制备方法及其中间体 |
| CN106366016B (zh) * | 2015-07-22 | 2019-03-05 | 连云港润众制药有限公司 | 一种碘普罗胺的制备方法及其中间体 |
| EP3704130A4 (en) | 2017-11-01 | 2021-07-07 | Melinta Therapeutics, Inc. | SUMMARY OF BORONATE ESTERS DERIVATIVES AND ASSOCIATED USES |
| CN109293526A (zh) * | 2018-10-23 | 2019-02-01 | 湖北天舒药业有限公司 | 一种碘帕醇的合成及其合成中间体的制备 |
| CA3170224A1 (en) * | 2020-02-14 | 2021-08-19 | Solvay Sa | New frothers for minerals recovery and methods of making and using same |
| GB202009917D0 (en) * | 2020-06-29 | 2020-08-12 | Ge Healthcare As | Process for the preparation of iopamidol |
| JP2024514435A (ja) | 2021-03-22 | 2024-04-02 | ブラッコ・イメージング・ソシエタ・ペル・アチオニ | セリノールの工業的合成 |
| EP4452931A1 (en) | 2021-12-20 | 2024-10-30 | Bracco Imaging SPA | Process for the preparation of 2,4,6-triiodoisophthalic bisamides |
| CN115010617B (zh) * | 2022-07-11 | 2024-06-11 | 安徽普利药业有限公司 | 一种碘帕醇的制备方法 |
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| IT1256162B (it) | 1992-10-27 | 1995-11-29 | Zambon Spa | Processo per la preparazione di un intermedio della sintesi organica |
| IT1274027B (it) | 1994-03-03 | 1997-07-14 | Zambon Spa | Processo per la preparazione e purificazione di mezzi di contrasto iodurati |
| IT1274676B (it) * | 1994-04-14 | 1997-07-24 | Zambon Spa | Processo per la preparazione di 5-ammino-2,2-dialchil-1,3-diossani |
| IT1282674B1 (it) | 1996-02-23 | 1998-03-31 | Bracco Spa | Processo per la purificazione di agenti contrastografici opacizzanti |
| US5763650A (en) | 1995-05-23 | 1998-06-09 | Fructamine S.P.A. | Process for the preparation of a halosubstituted aromatic acid |
| WO1996037460A1 (en) | 1995-05-23 | 1996-11-28 | Fructamine S.P.A. | Process for the preparation of a dicarboxylic acid dichloride |
| SI9620012A (en) | 1995-05-23 | 1997-06-30 | Fructamine Spa | Process for the preparation of a dicarboxylic acid dichloride |
| IT1288114B1 (it) | 1996-06-13 | 1998-09-10 | Fructamine Spa | Processo per la purificazione di un intermedio |
| IT1286522B1 (it) | 1996-12-04 | 1998-07-15 | Dibra Spa | Processo per la preparazione di derivati dell'acido 5-ammino-2,4,6- triiodo-1,3-benzenedicarbossilico |
| IT1289520B1 (it) * | 1996-12-24 | 1998-10-15 | Zambon Spa | Processo per la preparazione di un intermedio utile nella sintesi di mezzi di contrasto iodurati |
| GB2331098A (en) | 1997-11-07 | 1999-05-12 | Nycomed Imaging As | An N-Alkylation process |
| IT1299202B1 (it) | 1998-05-08 | 2000-02-29 | Dibra Spa | Processo per la preparazione della s-n,n'-bis (2-idrossi-1- (idrossimetil)etil) -5-((2-idrossi-1-ossopropil)ammino)-2,4,6-triiodo |
| GB9825095D0 (en) | 1998-11-16 | 1999-01-13 | Nycomed Imaging As | Chemical process |
| US6803485B2 (en) * | 1999-02-26 | 2004-10-12 | Bracco Imaging S.P.A. | Process for the preparation of iopamidol |
| IT1319671B1 (it) * | 2000-12-01 | 2003-10-23 | Bracco Spa | Processo per la preparazione di (s)-n,n'-bis(2-idrossi-1-(idrossimetil)etil)-5-((2-idrossi-1-ossopropil)ammino) |
| IT1319670B1 (it) * | 2000-12-01 | 2003-10-23 | Bracco Spa | Processo per la preparazione di 5-ammino-n,n'-bis(2-idrossi-1-(idrossimetil)etil))-1,3-benzendicarbossammide (i) e 5-ammino-n,n'- |
| WO2005019229A1 (en) * | 2003-08-26 | 2005-03-03 | Biocon Limited | Process for purification of boronic acid and its derivatives |
| ZA200803812B (en) | 2005-10-21 | 2009-09-30 | Video Taped Transcripts Pty Lt | A method of producing perforated retroreflective trim |
| EP2093206A1 (en) | 2008-02-20 | 2009-08-26 | BRACCO IMAGING S.p.A. | Process for the iodination of aromatic compounds |
| BRPI0921464B8 (pt) | 2008-11-18 | 2021-05-25 | Bracco Imaging Spa | processo para preparação de agente de contraste iodado |
| EP2243767A1 (en) | 2009-04-21 | 2010-10-27 | Bracco Imaging S.p.A | Process for the iodination of aromatic compounds |
| SI2451994T1 (sl) | 2009-07-07 | 2014-03-31 | Bracco Imaging Spa | Postopek za pripravo jodirnega sredstva |
| EP2394984A1 (en) | 2010-06-10 | 2011-12-14 | Bracco Imaging S.p.A | Process for the iodination of phenolic derivatives |
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2014
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