CN115557846B - 8-氨基辛酸的合成方法 - Google Patents
8-氨基辛酸的合成方法 Download PDFInfo
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- UQXNEWQGGVUVQA-UHFFFAOYSA-N 8-aminooctanoic acid Chemical compound NCCCCCCCC(O)=O UQXNEWQGGVUVQA-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 229940125782 compound 2 Drugs 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 11
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 11
- 239000012279 sodium borohydride Substances 0.000 claims description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- -1 methoxy, isopropoxy Chemical group 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 238000000354 decomposition reaction Methods 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- 239000012266 salt solution Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 15
- 239000000543 intermediate Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
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- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 description 7
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000000105 evaporative light scattering detection Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229940125796 compound 3d Drugs 0.000 description 4
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 2
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- IIRFCWANHMSDCG-UHFFFAOYSA-N cyclooctanone Chemical compound O=C1CCCCCCC1 IIRFCWANHMSDCG-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- OEIJHBUUFURJLI-UHFFFAOYSA-N octane-1,8-diol Chemical compound OCCCCCCCCO OEIJHBUUFURJLI-UHFFFAOYSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- 125000003816 2-hydroxybenzoyl group Chemical group OC1=C(C(=O)*)C=CC=C1 0.000 description 1
- ORLDOAAXBULOSV-UHFFFAOYSA-N 3,4,5,6,7,8-hexahydro-2h-azonine Chemical compound C1CCCC=NCCC1 ORLDOAAXBULOSV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GMXIEASXPUEOTG-UHFFFAOYSA-N 8-bromooctan-1-ol Chemical compound OCCCCCCCCBr GMXIEASXPUEOTG-UHFFFAOYSA-N 0.000 description 1
- BKJFDZSBZWHRNH-UHFFFAOYSA-N 8-bromooctanoic acid Chemical compound OC(=O)CCCCCCCBr BKJFDZSBZWHRNH-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
-
- 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
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明提供了8‑氨基辛酸的合成方法,涉及药物合成领域。本发明首先提供了一种制备8‑氨基辛酸的中间体,所述中间体是式I所示的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物。还提供了利用该中间体合成8‑氨基辛酸的方法。本发明合成方法所使用的主要原料便宜易得、使用安全,合成步骤简单,产品收率和纯度高,适合于大规模工业生产,具有良好的应用前景。
Description
技术领域
本发明涉及药物合成领域,具体涉及8-氨基辛酸的合成方法。
背景技术
SNAC,即N-(8-[2-羟基苯甲酰基]-氨基)辛酸钠,它是一种化学合成的脂肪酸衍生物,最早是由Emisphere公司在众多促渗透剂中筛选出来的高效分子。分子式为C15H20NNaO4,Mw=301Da,pKa=5.0。
早在1990s,Emisphere公司研发团队认为SNAC通过非共价键形式与API结合后,可使API构型改变,暴露出更多疏水区域,从而促进API的跨细胞膜渗透。2006年,Emisphere团队提出SNAC的作用模式假说:载体分子SNAC与药物分子结合,形成可运输的复合物(疏水亲脂性),从而进行跨细胞转运。同时,由于二者的弱关联作用,载体和药物在进入血液循环时通过简单的稀释而分离。临床数据已经证明了SNAC能促进有些多肽药物比如司美格鲁肽片剂的渗透和吸收,而且有较好的稳定性和安全性。由于口服多肽已逐渐成为多肽药物发展的未来趋势,SNAC作为促渗透剂引领口服多肽从无到有巨大的应用潜力。
8-氨基辛酸(CAS:1002-57-9)是SNAC的关键中间体,结构如下:
到目前为止,已经报道的合成8-氨基辛酸的方法主要有以下几种:
(1)Eshghi,Hossein等以环辛酮为原料,经叠氮化钠和浓硫酸重排制备2-氮杂环壬酮,再经过酸水解得到8-氨基辛酸(Journal of Chemical Research,2006,4,218),合成路线如下:
该方法的缺点是原料环辛酮价格比较贵,而且反应要用到叠氮化钠,该原料易制爆,而且在酸中会产生剧毒的叠氮酸,放大生产会有很大的安全隐患,因此只能在实验室中小批量合成,无法工业化。
(2)Nanda等以辛二醇为原料,与氢溴酸反应得到8-溴-1-辛醇,再经Jones试剂氧化得到8-溴-1-辛酸,最后与氨水反应得到8-氨基辛酸(Tetrahedron Asymmetry,2003,14,13,1799),合成路线如下:
该方法的局限在于起始原料辛二醇价格较贵,而且氧化剂Jones试剂含有重金属铬元素,会产生含有铬盐的废固,这会对环境造成严重的污染。因此该方法不适合大规模生产。
目前8-氨基辛酸的合成工艺存在原料价格贵,危险易制爆,对环境影响大等问题,不适合生产放大。因此开发出一种原料价格低廉且安全,收率高,绿色环保,适合工业化生产的合成8-氨基辛酸的方法,对于大批量生产8-氨基辛酸具有重要意义。
发明内容
为了解决上述问题,本发明提供了一种8-氨基辛酸的合成方法。
本发明首先提供了式I所示的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物:
其中,R选自C1~C4烷基、C1~C4烷氧基。
进一步地,R选自甲基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基。
本发明还提供了前述的化合物的制备方法,它包括如下步骤:
(1)在碱存在下,化合物1和乙酸乙酯在溶剂中发生开环反应得到化合物2;
(2)催化剂作用下,化合物2和对甲苯磺酰肼在溶剂中反应,然后用醋酸硼氢化钠还原,得到式I所示化合物。
进一步地,
步骤(1)中,所述化合物1、乙酸乙酯和碱的摩尔比为1:(2.0~2.5):(2.0~2.5);
和/或,步骤(2)中,所述化合物2、对甲苯磺酰肼、催化剂和醋酸硼氢化钠的摩尔比为1:(1.0~1.1):(0.1~0.2):(2.0~2.5);
优选地,
步骤(1)中,所述化合物1、乙酸乙酯和碱的摩尔比为1:2.2:2.2;
和/或,步骤(2)中,所述化合物2、对甲苯磺酰肼、催化剂和醋酸硼氢化钠的摩尔比为1:1.0:0.1:2.0。
进一步地,
步骤(1)中,所述碱为KHMDS或LDA;
和/或,步骤(1)中,所述溶剂为四氢呋喃;
和/或,步骤(2)中,所述催化剂为三氟乙酸、硫酸或对甲苯磺酸;
和/或,步骤(2)中,所述溶剂为甲苯;
和/或,步骤(1)中,所述反应温度为-80~-70℃;
和/或,步骤(2)中,所述在溶剂中反应的温度为100~110℃;
和/或,步骤(2)中,所述还原温度为100~110℃;
优选地,
步骤(1)中,所述反应时间为3~4小时;
和/或,步骤(2)中,所述在溶剂中反应的时间为1~12小时;
和/或,步骤(2)中,所述还原时间为1~4小时。
进一步地,
步骤(1)中,所述乙酸乙酯先滴加到碱中,然后滴入溶解在溶剂中的化合物1中反应;
优选地,
步骤(1)中,所述乙酸乙酯滴加到碱中后于-80~-70℃搅拌30~60min。
进一步地,
步骤(1)中,所述反应后包括如下提纯步骤:将反应液依次淬灭、萃取、洗涤、浓缩至干;
和/或,步骤(2)中,所述还原后包括如下提纯步骤:将反应液降温、洗涤、浓缩至干。
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物作为中间体原料制备8-氨基辛酸的用途。
本发明还提供了8-氨基辛酸的合成方法,它包括如下步骤:
其中,R选自C1~C4烷基、C1~C4烷氧基;
式I所示化合物在酸中脱保护后用环氧丙烷解盐得到8-氨基辛酸;
优选地,R选自甲基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基。
进一步地,
所述式I所示化合物、环氧丙烷的摩尔比为1:(1.0~2.0);
和/或,所述式I所示化合物和酸的质量体积比为1g:(5.0~8.0)mL;
优选地,
所述式I所示化合物、环氧丙烷的摩尔比为1:1.5;
和/或,所述式I所示化合物和酸的质量体积比为1g:6mL。
进一步地,
所述酸为盐酸;
和/或,所述脱保护的温度为100~105℃;
和/或,所述解盐的温度为20~30℃;
优选地,
所述脱保护的时间为10~12小时;
和/或,所述解盐的时间为1-2小时。
进一步地,
所述盐解后包括如下提纯步骤:将反应液过滤后干燥滤饼。
与现有技术相比,本发明的有益效果为:
本发明首先提供了一种制备8-氨基辛酸的中间体,然后提供了一种8-氨基辛酸的合成方法,本发明合成方法所使用的主要原料便宜易得、使用安全,合成步骤简单,产品收率和纯度高,适合于大规模工业生产,具有良好的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为8-氨基辛酸的HNMR(D2O)图谱。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
本发明按照以下反应路线制备8-氨基辛酸:
实施例1、制备8-氨基辛酸(R=t-Bu)
步骤1:化合物2a的制备:
将1M KHMDS(981g,1.115mol,2.2eq)加入反应瓶中,氮气保护下降温至-80~-70℃。滴加乙酸乙酯(98.2g,1.115mol,2.2eq),控温-80~-70℃。滴毕,搅拌30min。将化合物1a(100.0g,0.507mol,1.0eq)溶于四氢呋喃(500mL)中滴入,控温-80~-70℃,在1h内滴完。滴毕,搅拌3-4h至原料消失。将反应液淬灭至15%柠檬酸水溶液(1000mL)中,用乙酸乙酯(500mLx3)萃取,有机相合并分别用水(500mL)和饱和食盐水(500mL)洗涤,有机相浓缩至干得化合物2a(117.2g,0.411mol),收率81%。
步骤2:化合物3a的制备:
将化合物2a(100.0g,0.350mol,1.0eq),对甲苯磺酰肼(65.3g,0.350mol,1.0eq),浓硫酸(3.43g,0.035mol,0.1eq),甲苯(800mL)加入反应瓶中。氮气保护下,升温至100-110℃反应4h,期间将生成的水分出。之后分批加入醋酸硼氢化钠(148.4g,0.7mol,2.0eq),继续在100-110℃搅拌2h。降至室温,用5%碳酸氢钠水溶液(400mL)洗涤,水(300mL)洗涤,有机相减压浓缩至干得化合物3a(87.4g,0.322mol),收率92%。
HNMR(CDCl3)数据为:5.55(br,1H),4.05(t,J=8.0Hz,2H),3.15(m,2H),2.22(t,J=8.0Hz,2H),1.31-1.62(m,4H),1.12-1.25(m,18H).
步骤3:化合物4的制备:
将化合物3a(80g,0.295mol,1.0eq),浓盐酸(480mL)加入反应瓶中,升温至100-105℃反应12h。将反应液减压浓缩至干。加入乙醇(320mL),加入环氧丙烷(25.68g,0.442mol,1.5eq),室温搅拌1-2h,过滤,滤饼干燥得化合物4(40.9g,0.257mol),收率87%。
合成化合物4的总收率为64.8%,化合物4的纯度为99.9%(ELSD)。
实施例2、制备8-氨基辛酸(R=Me)
步骤1:化合物2b的制备:
将1M KHMDS(1247g,1.417mol,2.2eq)加入反应瓶中,氮气保护下降温至-80~-70℃。滴加乙酸乙酯(124.8g,1.417mol,2.2eq),控温-80~-70℃。滴毕,搅拌30min。将化合物1b(100g,0.644mol,1.0eq)溶于四氢呋喃(500mL)中滴入,控温-80~-70℃,在1h内滴完。滴毕,搅拌3-4h至原料消失。将反应液淬灭至15%柠檬酸水溶液(1000mL)中,用乙酸乙酯(500mLx3)萃取,有机相合并分别用水(500mL)和饱和食盐水(500mL)洗涤,有机相浓缩至干得化合物2b(115.9g,0.477mol),收率74%。
步骤2:化合物3b的制备:
将化合物2b(100g,0.411mol,1.0eq),对甲苯磺酰肼(76.5g,0.411mol,1.0eq),浓硫酸(4.0g,0.041mol,0.1eq),甲苯(800mL)加入反应瓶中。氮气保护下,升温至100-110℃反应4h,期间将生成的水分出。之后分批加入醋酸硼氢化钠(174.2g,0.822mol,2.0eq),继续在100-110℃搅拌2h。降至室温,用5%碳酸氢钠水溶液(400mL)洗涤,水(300mL)洗涤,有机相减压浓缩至干得化合物3b(82.9g,0.362mol),收率88%。
HNMR(CDCl3)数据为:5.67(br,1H),4.11(t,J=8.0Hz,2H),3.22(m,2H),2.30(t,J=8.0Hz,2H),1.97(s,3H),1.47-1.63(m,4H),1.24-1.32(m,9H).
步骤3:化合物4的制备:
将化合物3b(80g,0.349mol,1.0eq),浓盐酸(480mL)加入反应瓶中,升温至100-105℃反应12h。将反应液减压浓缩至干。加入乙醇(300mL),加入环氧丙烷(30.4g,0.524mol,1.5eq),室温搅拌1-2h,过滤,滤饼干燥得化合物4(48.9g,0.307mol),收率88%。
合成化合物4的总收率为57.3%,化合物4的纯度为99.9%(ELSD)。
实施例3、制备8-氨基辛酸(R=OMe)
步骤1:化合物2c的制备:
将1M KHMDS(1130.8g,1.285mol,2.2eq)加入反应瓶中,氮气保护下降温至-80~-70℃。滴加乙酸乙酯(113.2g,1.285mol,2.2eq),控温-80~-70℃。滴毕,搅拌30min。将化合物1c(100g,0.584mol,1.0eq)溶于四氢呋喃(500mL)中滴入,控温-80~-70℃,在1h内滴完。滴毕,搅拌3-4h至原料消失。将反应液淬灭至15%柠檬酸水溶液(1000mL)中,用乙酸乙酯(500mLx3)萃取,有机相合并分别用水(500mL)和饱和食盐水(500mL)洗涤,有机相浓缩至干得化合物2c(125.7g,0.485mol),收率83%。
步骤2:化合物3c的制备:
将化合物2c(100g,0.386mol,1.0eq),对甲苯磺酰肼(71.8g,0.386mol,1.0eq),浓硫酸(3.8g,0.0386mol,0.1eq),甲苯(800mL)加入反应瓶中。氮气保护下,升温至100-110℃反应4h,期间将生成的水分出。之后分批加入醋酸硼氢化钠(163.6g,0.772mol,2.0eq),继续在100-110℃搅拌2h。降至室温,用5%碳酸氢钠水溶液(400mL)洗涤,水(300mL)洗涤,有机相减压浓缩至干得化合物3c(87.1g,0.355mol),收率92%。
HNMR(CDCl3)数据为:4.65(br,1H),4.12(t,J=8.0Hz,2H),3.66(s,3H),3.21(m,2H),2.28(t,J=8.0Hz,2H),1.48-1.63(m,5H),1.24-1.31(m,8H).
步骤3:化合物4的制备:
将化合物3c(80g,0.326mol,1.0eq),浓盐酸(480mL)加入反应瓶中,升温至100-105℃反应12h。将反应液减压浓缩至干。加入乙醇(300mL),加入环氧丙烷(28.4g,0.489mol,1.5eq),室温搅拌1-2h,过滤,滤饼干燥得化合物4(42.6g,0.267mol),收率82%。
合成化合物4的总收率为62.6%,化合物4的纯度为99.9%(ELSD)。
实施例4、制备8-氨基辛酸(R=Ot-Bu)
步骤1:化合物2d的制备:
将1M KHMDS(908.2g,1.032mol,2.2eq)加入反应瓶中,氮气保护下降温至-80~-70℃。滴加乙酸乙酯(90.9g,1.032mol,2.2eq),控温-80~-70℃。滴毕,搅拌30min。将化合物1d(100g,0.469mol,1.0eq)溶于四氢呋喃(500mL)中滴入,控温-80~-70℃,在1h内滴完。滴毕,搅拌3-4h至原料消失。将反应液淬灭至15%柠檬酸水溶液(1000mL)中,用乙酸乙酯(500mLx3)萃取,有机相合并分别用水(500mL)和饱和食盐水(500mL)洗涤,有机相浓缩至干得化合物2d(120.1g,0.399mol),收率85%。
步骤2:化合物3d的制备:
将化合物2d(100g,0.332mol,1.0eq),对甲苯磺酰肼(61.8g,0.332mol,1.0eq),浓硫酸(3.3g,0.033mol,0.1eq),甲苯(800mL)加入反应瓶中。氮气保护下,升温至100-110℃反应4h,期间将生成的水分出。之后分批加入醋酸硼氢化钠(140.7g,0.664mol,2.0eq),继续在100-110℃搅拌2h。降至室温,用5%碳酸氢钠水溶液(400mL)洗涤,水(300mL)洗涤,有机相减压浓缩至干得化合物3d(88.7g,0.309mol),收率93%。
HNMR(CDCl3)数据为:4.54(br,1H),4.13(t,J=8.0Hz,2H),3.08-3.16(m,2H),2.28(t,J=8.0Hz,2H),1.60(m,2H),1.44(s,9H),1.22-1.32(m,11H).
步骤3:化合物4的制备:
将化合物3d(80g,0.278mol,1.0eq),浓盐酸(480mL)加入反应瓶中,升温至100-105℃反应12h。将反应液减压浓缩至干。加入乙醇(300mL),加入环氧丙烷(24.3g,0.418mol,1.5eq),室温搅拌1-2h,过滤,滤饼干燥得化合物4(37.2g,0.234mol),收率84%。
合成化合物4的总收率为66.4%,化合物4的纯度为99.9%(ELSD)。
实施例5、制备8-氨基辛酸(R=Ot-Bu)放大例
步骤1:化合物2d的制备:
将1M KHMDS(90.82kg,103.2mol,2.2eq)加入500L低温釜中,氮气保护下降温至-80~-70℃。滴加乙酸乙酯(9.09kg,103.2mol,2.2eq),控温-80~-70℃。滴毕,搅拌30min。将化合物1d(10.0kg,46.9mol,1.0eq)溶于四氢呋喃(50L)中滴入,控温-80~-70℃,在1h内滴完。滴毕,搅拌3-4h至原料消失。将反应液淬灭至15%柠檬酸水溶液(100L)中,用乙酸乙酯(50L x3)萃取,有机相合并分别用水(50L)和饱和食盐水(50L)洗涤,有机相浓缩至干得化合物2d(12.4kg,41.3mol),收率88%。
步骤2:化合物3d的制备:
将化合物2d(12.4kg,41.3mol,1.0eq),对甲苯磺酰肼(7.69kg,41.3mol,1.0eq),浓硫酸(404.7g,4.13mol,0.1eq),甲苯(99.2L)加入500L反应釜中。氮气保护下,升温至100-110℃反应8-12h,期间将生成的水分出。之后分批加入醋酸硼氢化钠(17.51kg,82.6mol,2.0eq),继续在100-110℃搅拌4h。降至室温,用5%碳酸氢钠水溶液(50L)洗涤,水(37L)洗涤,有机相减压浓缩至干得化合物3d(11.28kg,39.235mol),收率95%。
步骤3:化合物4的制备:
将化合物3d(11.28kg,39.235mol,1.0eq),浓盐酸(68L)加入反应瓶中,升温至100-105℃反应12h。将反应液减压浓缩至干。加入乙醇(45L),加入环氧丙烷(3.41kg,58.85mol,1.5eq),室温搅拌1-2h,过滤,滤饼干燥得化合物4(5.44kg,34.13mol),收率87%。
合成化合物4的总收率为72.7%,化合物4的纯度为99.9%(ELSD)。
本发明制备得到的8-氨基辛酸的HNMR(D2O)图谱如图1所示,HNMR(D2O)数据为:2.97(t,J=6.0Hz,2H),2.17(t,J=6.0Hz,2H),1.37(m,10H).
综上,本发明首先提供了一种制备8-氨基辛酸的中间体,然后提供了一种8-氨基辛酸的合成方法,本发明合成方法所使用的主要原料便宜易得、使用安全,合成步骤简单,产品收率和纯度高,适合于大规模工业生产,具有良好的应用前景。
Claims (14)
1.式I所示的化合物、或其盐:
其中,
R选自甲基、叔丁基、甲氧基、异丙氧基、叔丁氧基。
2.式I所示的化合物的制备方法,其特征在于:它包括如下步骤:
(1)在碱存在下,化合物1和乙酸乙酯在溶剂中发生开环反应得到化合物2;
(2)催化剂作用下,化合物2和对甲苯磺酰肼在溶剂中反应,然后用醋酸硼氢化钠还原,得到式I所示化合物;
步骤(1)中,所述碱为KHMDS或LDA;
步骤(2)中,所述催化剂为三氟乙酸、硫酸或对甲苯磺酸;
R选自甲基、叔丁基、甲氧基、异丙氧基、叔丁氧基。
3.根据权利要求2所述的制备方法,其特征在于:
步骤(1)中,所述化合物1、乙酸乙酯和碱的摩尔比为1:(2.0~2.5):(2.0~2.5);
和/或,步骤(2)中,所述化合物2、对甲苯磺酰肼、催化剂和醋酸硼氢化钠的摩尔比为1:(1.0~1.1):(0.1~0.2):(2.0~2.5)。
4.根据权利要求3所述的制备方法,其特征在于:
步骤(1)中,所述化合物1、乙酸乙酯和碱的摩尔比为1:2.2:2.2;
和/或,步骤(2)中,所述化合物2、对甲苯磺酰肼、催化剂和醋酸硼氢化钠的摩尔比为1:1.0:0.1:2.0。
5.根据权利要求2所述的制备方法,其特征在于:
步骤(1)中,所述溶剂为四氢呋喃;
和/或,步骤(2)中,所述溶剂为甲苯;
和/或,步骤(1)中,所述反应温度为-80~-70℃;
和/或,步骤(2)中,所述在溶剂中反应的温度为100~110℃;
和/或,步骤(2)中,所述还原温度为100~110℃。
6.根据权利要求5所述的制备方法,其特征在于:
步骤(1)中,所述反应时间为3~4小时;
和/或,步骤(2)中,所述在溶剂中反应的时间为1~12小时;
和/或,步骤(2)中,所述还原时间为1~4小时。
7.根据权利要求2所述的制备方法,其特征在于:
步骤(1)中,所述反应后包括如下提纯步骤:将反应液依次淬灭、萃取、洗涤、浓缩至干;
和/或,步骤(2)中,所述还原后包括如下提纯步骤:将反应液降温、洗涤、浓缩至干。
8.权利要求1所述的化合物、或其盐作为中间体原料制备8-氨基辛酸的用途。
9.8-氨基辛酸的合成方法,其特征在于:它包括如下步骤:
其中,R选自C1~C4烷基、C1~C4烷氧基;
式I所示化合物在酸中脱保护后用环氧丙烷解盐得到8-氨基辛酸。
10.根据权利要求9所述的合成方法,其特征在于:R选自甲基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基。
11.根据权利要求9所述的合成方法,其特征在于:
所述式I所示化合物、环氧丙烷的摩尔比为1:(1.0~2.0);
和/或,所述式I所示化合物和酸的质量体积比为1g:(5.0~8.0)mL。
12.根据权利要求11所述的合成方法,其特征在于:
所述式I所示化合物、环氧丙烷的摩尔比为1:1.5;
和/或,所述式I所示化合物和酸的质量体积比为1g:6mL。
13.根据权利要求9所述的合成方法,其特征在于:所述酸为盐酸;
和/或,所述脱保护的温度为100~105℃;
和/或,所述解盐的温度为20~30℃;
和/或,所述盐解后包括如下提纯步骤:将反应液过滤后干燥滤饼。
14.根据权利要求13所述的合成方法,其特征在于:
所述脱保护的时间为10~12小时;
和/或,所述解盐的时间为1-2小时。
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