CN113412255A - 制备4-氨基-5-甲基吡啶酮的方法 - Google Patents
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- SSQZBQXJYGNUSC-UHFFFAOYSA-N 4-amino-5-methyl-1h-pyridin-2-one Chemical compound CC1=CNC(=O)C=C1N SSQZBQXJYGNUSC-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 49
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 23
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical class [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims abstract description 16
- DOTGZUGIZALMLZ-UHFFFAOYSA-N 4-hydroxy-5-methyl-1h-pyridin-2-one Chemical compound CC1=CNC(O)=CC1=O DOTGZUGIZALMLZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- WFWSVBNEGRBFSD-UHFFFAOYSA-N 2,6-dimethylpyridin-1-ium;bromide Chemical compound Br.CC1=CC=CC(C)=N1 WFWSVBNEGRBFSD-UHFFFAOYSA-N 0.000 claims description 2
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 150000005621 tetraalkylammonium salts Chemical class 0.000 claims description 2
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 claims description 2
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical compound [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 claims description 2
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 claims description 2
- AISMNBXOJRHCIA-UHFFFAOYSA-N trimethylazanium;bromide Chemical compound Br.CN(C)C AISMNBXOJRHCIA-UHFFFAOYSA-N 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 28
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000013341 scale-up Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000380131 Ammophila arenaria Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- NKMJTBQLPWUPGU-UHFFFAOYSA-N C1(=CCNC=C1C)N Chemical compound C1(=CCNC=C1C)N NKMJTBQLPWUPGU-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 1
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical compound N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及一种制备方法中间体式(I)的4‑氨基‑5‑甲基吡啶酮的方法，其特征在于使中间体式(III)的4‑羟基‑5‑甲基‑1H‑吡啶‑2‑酮与氨在添加溴化铵盐的情况下在高压釜中反应。
Description
本发明涉及一种新的和改进的制备式(I)的4-氨基-5-甲基吡啶酮的方法
式(I)的化合物是用于制备非奈利酮(finerenone)(II)的关键中间体：
非奈利酮(II)作为盐皮质激素受体的非甾体拮抗剂，并且可用作预防和/或治疗心血管和肾脏疾病例如心力衰竭和糖尿病肾病的药剂。
式(II)的化合物及其制备方法记载于WO 2008/104306 A1和ChemMedChem 2012,7,1385以及WO 2016/016287 A1(Bayer Pharma AG)中，这些出版物均公开了对研究合成的详细讨论。其中所述合成的缺点在于，该合成不适合用于进一步的工业规模方法，因为许多步骤在非常高的稀释度下，使用非常高过量的试剂进行，从而导致总收率相对较低。
因此，需要这样的合成，其能够以工业规模实施，并且以高总收率、低生产成本和高纯度可再现地提供式(I)的方法中间体，并且满足所有监管要求，以便提供使用活性物质的临床试验并用于后续监管提交。
化合物(I)的制备记载于Synthesis,第765页(1984)(实施例3c)中。从记载于Synthesis中的出版物的实施例1c中的羟基吡啶酮(III)开始，在沸腾的苄胺(IV)中反应得到化合物(V)。然后通过经由钯/碳的催化氢化反应将化合物(V)中的苄基水解裂解。经过两个步骤的总收率为理论值的62.4％。
所述方法的缺点是使用极大过量的苄胺：对于30mmol的式(III)的化合物，使用30ml(275.2mmol)苄胺，这基于化合物(III)计过量9.17倍。过量苄胺的回收利用耗时费力并伴随着高昂的成本。反应在沸腾的苄胺(185℃)中进行，反应时间为36小时。这样的高温在标准搅拌设备中不可行，而是需要特殊的技术设备。在重复该步骤时，特别观察到副产物(VI)，这归因于来自(III)的前体的痕量钯：
在严苛的反应条件下，脱氢为苄亚胺，然后分解为苯甲醛(在反应过程中形成水)，苯甲醛与化合物(III)缩合形成化合物(VI)。该副产物特别在批量放大规模时形成(最高达>10％)，并一直带至化合物(I)。反应溶液通过冷却至室温，用甲基乙基酮和邻二氯苯洗涤沉淀的晶体，然后从邻二氯苯中重结晶进行后处理。本文中，放弃氯化溶剂而追求更环保的变体也会是有利的。
后续脱苄基反应在冰乙酸中进行，10mmol于200ml中，即2.14g化合物(V)于200ml中。这相当于过量93.45倍。这意味着，对于1kg(V)，将需要93.45L乙酸。这些都是工业方法中不可能出现的极大过量。此外，对于10mmol(V)的转化，使用600mg碳载Pd催化剂(10％和30％)。这意味着，为了使1kg化合物(V)脱苄基化，将需要280g催化剂。从工业和经济角度来看，这也是不切实际的。为了后处理，将催化剂滤出并将滤液蒸发至干，通过与甲苯共沸除去痕量乙酸，并将残余物溶于丙酮或甲基乙基酮中并过滤。由于搅拌设备不会蒸发至干，因此该方法在放大规模(upscaling)时在技术上不可行。此外，分离需要三种不同的溶剂。然后通过色谱法(二氯甲烷/MeOH 1:1)进一步纯化强烈着色的反应产物，这是工业规模方法中可能需要避免的其他事项。
因此，所解决的问题是开发作为用于制备式(II)的化合物(finerenone)的中间体的方法中间体4-氨基-5-甲基吡啶酮的替代合成方法，特别是易于以工业规模实施、具有成本效益并避免大量过量溶剂且使用更环保的试剂的方法。
还应避免使用涉及色谱法的纯化步骤。
本发明发现了一种无需使用色谱法的非常有效的更短的合成方法，其可以避免上述缺点。通过使化合物(III)与氨在添加溴化铵盐的情况下反应，可以直接将氨基引入化合物(III)中。
苯酚与氨的反应记载于以下文献中：EP 2543654 A1,2013(Sumitomo RubberIndustries,Ltd)记载了例如苯酚与氨在450℃下的反应(21.2％收率)；在类似严苛条件下的类似方法记载于I.G.Farbenind.专利：DE570365,1930；Fortschr.Teerfarbenfabr.Verw.Industriezweige,第18卷,第446页和Fischer；Bahr；Wiedeking Brennstoff-Chemie,1934,第15卷,第101、103页。还记载于Chem.News J.Ind.Sci.,1867,第16卷,第55页；Helv.chim.Acta,1924,第7卷,第282页；Gmelin Handbook:N:MVol.2,5.2.2,第490-493页。与萘化学相关的反应记载于WO2008/124812A1,2008和Chemistry-An Asian Journal,2010,第5卷,#9第2053-2061页以及US 2008/293766 A1,2008和EP 2075245 A2,2009和Synthetic Communications,2001,第31卷,#14第2143-2148页中。这些是布赫尔(Bucherer)反应的特例，并且不能应用于化合物(III)，关于此的其他出版物：SyntheticCommunications,2001,第31卷,#14第2143-2148页；Chemische Berichte,1924,第57卷,第1738页；Fortschr.Teerfarbenfabr.Verw.Industriezweige,第2卷,第185页；WO 2005/44786 A1,2005；Journal für Praktische Chemie(Leipzig),1908,第<2>78卷,第153页；Bulletin of the Korean Chemical Society,2012,第33卷,#2第387-392页；HelveticaChimica Acta,1926,第9卷,第957页；Tetrahedron Letters,2003,第44卷,#26第4819-4822页；US 4609760 A1,1986；US 4400537 A1,1983；Journal of the Society ofChemical Industry,London,1932,第51卷,第283页；Journal of the American ChemicalSociety,1944,第66卷,第210、214页；US 2376112,1942；American Chemical Journal,1893,第15卷,第40页；Chemische Berichte,1886,第19卷,第1751页；Journal of theAmerican Chemical Society,1942,第64卷,第1023页；Journal of Organic Chemistry,1992,第57卷,#10第2873-2876页。
文献中提及的所有方法的特征首先在于非常严苛的反应条件，例如高于300℃的温度，以及在某些情况下其特征在于低收率。添加亚硫酸盐进行的方法或根据布赫尔反应的转化不能用于从(III)制备化合物(I)。此外，迄今为止，高度取代的“吡啶苯酚”与氨的反应在文献中尚未有记载。
如果使化合物(III)例如与氨气直接在高压釜中在最高达180℃的温度下反应，则即使在24小时后也仅观察到非常低的向目标化合物(I)的转化。
出人意料地已发现，如果向反应中添加例如0.2至3当量、优选1当量的溴化铵盐(例如溴化铵、三甲胺-HBr、三乙胺-HBr、吡啶-HBr、二甲基吡啶-HBr)或溴化季铵盐、四烷基铵盐(例如四甲基溴化铵、四丙基溴化铵或四丁基溴化铵)，则反应可以在更加温和的条件下进行并且几乎完全转化(通常>90％转化)。优选使用溴化铵。这是因为这使所述反应直接在纯氨(作为试剂和溶剂)中进行。为此，向高压釜(高压反应器)中装入化合物(III)和上述溴化物之一，并冷凝进20至200当量、优选40至100当量、更优选40至60当量的氨。反应在150℃至200℃、优选160℃至180℃、更优选170℃的温度下进行；反应时间为10至40小时，优选15至25小时。在一个特别优选的实施方案中，在反应结束后，将过量的氨直接冷凝至第二个高压釜中，然后可以在第二个高压釜中重新进行上述反应。这确保了在充分利用氨的情况下所述方法的连续操作，即通过连续操作避免氨损失。从生态和经济角度来看，这与现有技术方法相比具有巨大的优势。
当蒸发出氨后，可将残余物溶于合适的溶剂中，之后可将产物通过结晶进行分离和纯化。合适的溶剂为水、醇类(例如甲醇、乙醇和正丁醇)及醇类与水的混合物。还可以例如将产物溶于少量乙酸中并用非极性溶剂(例如甲基叔丁基醚)使其沉淀。然而，优选从水中结晶(参见实施例1)，或在四烷基溴化铵的情况下，通过与正丁醇一起搅拌进行最终萃取(参见实施例2)。干燥后的分离收率通常为理论值的约70％(一个化学步骤)，并且高于现有技术中经过两个步骤的总收率(理论值的62.4％，参见上文)。母液通常仍包含约15-20％的产物，还可将其——特别是在放大规模的过程中——分离，从而将总收率显著提高至理论值的>70％。不需要现有技术中所述的色谱分离，从而使本发明的新方法就用于大规模生产的放大规模而言非常有吸引力。
因此，本发明提供一种制备方法中间体式(I)的4-氨基-5-甲基吡啶酮的方法，其特征在于使中间体式(III)的4-羟基-5-甲基-1H-吡啶-2-酮与氨在添加溴化铵盐的情况下在高压釜中反应。
实施例
实施例1
添加溴化铵制备4-氨基-5-甲基-1H-吡啶-2-酮(式(I)的化合物)
向压力反应器中装入4.0g(32mmol)4-羟基-5-甲基-1H-吡啶-2-酮(化合物III，其制备根据：Synthesis,第765页(1984))以及3.135g(32mmol)溴化铵，然后冷凝进27.00g(1.585mol)氨(液态)。将混合物在170℃下搅拌20小时(压力升至90巴)。为了后处理，蒸发过量的氨气并将残余物溶于16ml水中。然后将其加热至80℃，从而使残余物溶解。将溶液缓慢冷却，然后在0-5℃下搅拌2小时。将沉淀的晶体滤出，并在50℃的真空干燥箱中干燥过夜。
产量：2.70g(理论值的68.04％)结晶固体。
纯度约98％(HPLC，100％方法)
MS(EIpos)：m/z＝125[M+H]
1H-NMR(300MHz,DMSO-d6)：δ＝1.81(s,3H),2.54(s,1H),5.24(s,1H),5.79(s,2H),6.85(s,1H),10.27(br s,1H)
实施例2
添加四丁基溴化铵制备4-氨基-5-甲基-1H-吡啶-2-酮(式(I)的化合物)
向压力反应器中装入4.0g(32mmol)4-羟基-5-甲基-1H-吡啶-2-酮(化合物III，其制备根据：Synthesis,第765页(1984))以及10.32g(32mmol)四丁基溴化铵，然后冷凝进27.00g(1.585mol)氨(液态)。将混合物在170℃下搅拌20小时(压力升至70巴)。为了后处理，蒸发过量的氨气，并将残余物溶于100ml水中，并用1N盐酸水溶液将pH调节至pH 7.0，然后将不溶性杂质滤出。加入100ml正丁醇，并将混合物在室温下搅拌30分钟。将有机相分离出并再次用100ml水萃取。将水相合并在减压下浓缩至干。将残余物溶于10ml水中并进行萃取搅拌。将产物滤出，然后在30℃的真空干燥箱中干燥约72小时。然后将由此获得的产物通过与10ml正丁醇一起搅拌进行最终萃取，过滤并在50℃的真空干燥箱中干燥。获得结晶固体。
产量：2.80g(理论值的70.56％)结晶固体。
纯度约98％(HPLC，100％方法)
MS(EIpos)：m/z＝125[M+H]
1H-NMR(300MHz,DMSO-d6)：δ＝1.81(s,3H),2.54(s,1H),5.24(s,1H),5.79(s,2H),6.85(s,1H),10.27(br s,1H)
表1：实施例1和2与文献实施例(Synthesis,第765页,1984,实施例3c)的比较
从上文所述内容，显而易见的是，迄今为止可用的方法(如Synthesis,第765页,1984,实施例3c中所记载)的缺点在于：
(1)进行多步骤合成，
(2)形成式(VI)的副产物(最高达>10％)，其在式(I)的化合物中作为杂质出现，并且需要通过耗时费力的色谱法除去，
(3)以极大过量使用苄胺，其回收利用耗时费力并伴随着高昂的成本，
(4)反应需要在185℃下在沸腾的苄胺中进行，并且反应时间为36小时，由于这样的高温在标准搅拌装置中不可行，因此需要特殊的技术设备，
(5)使用氯化溶剂，不环保，并且
(6)需要使用大量的碳载Pd催化剂，其分离和处理不仅耗时费力，而且在工业规模合成中几乎不可行。
相比之下，本发明的方法避免了这些缺点，并且实现了以下效果和优点：
(1)只进行一个工艺步骤，
(2)式(III)的化合物在干燥后的分离收率通常为理论值的约70％(一个化学步骤)，并且高于现有技术中经过两个步骤的总收率(理论值的62.4％，Synthesis,第765页,1984,实施例3c)，
(3)本发明的方法中获得的母液通常仍包含约15-20％的产物，还可将其——特别是在放大规模的过程中——分离，从而可将总收率显著提高至理论值的>70％，
(4)式(I)的化合物直接以高纯度结晶产物获得，而无需纯化，
(5)避免使用碳载Pd催化剂，
(6)式(VI)的化合物不会作为不希望的副产物形成，
(7)不需要现有技术中所述的色谱分离，从而使本发明的新方法就用于大规模生产的放大规模而言非常有吸引力，
(8)不需要现有技术中所述的色谱纯化，因为不会形成不希望的式(VI)的副产物，
(9)可以部分或全部消除溶剂，特别是氯化溶剂的重复使用，从而使本发明的方法更加环保，并且
(10)需要更短的反应时间和/或更低的反应温度。
总体而言，本发明的方法代表了一种无需使用色谱法的非常有效的更短的合成方法，其还适用于放大规模。通过使式(III)的化合物与氨在添加溴化铵盐的情况下反应，可以直接将氨基引入式(III)的化合物中。
以下段落描述了本发明的实施方案：
(1.)制备方法中间体式(I)的4-氨基-5-甲基吡啶酮的方法，其特征在于使中间体式(III)的4-羟基-5-甲基-1H-吡啶-2-酮与氨在添加溴化铵盐的情况下在高压釜中反应。
(2.)根据第1段所述的方法，其特征在于所述反应在150℃至200℃下进行。
(3.)根据第1或2段所述的方法，其特征在于使用溴化铵。
(4.)根据第1至3段中任一项所述的方法，其特征在于使用1当量的溴化铵盐。
(5.)根据第1至4段中任一项所述的方法，其特征在于使用20至200当量的氨。
(6.)根据第1至5段中任一项所述的方法，其特征在于，在反应结束后，将过量的氨直接冷凝至第二个高压釜中，然后在第二个高压釜中进行第1至5段所述的反应。
Claims (12)
1.制备方法中间体式(I)的4-氨基-5-甲基吡啶酮的方法，
其中使中间体式(III)的4-羟基-5-甲基-1H-吡啶-2-酮与氨在添加溴化铵盐的情况下在高压釜中反应
2.根据权利要求1所述的方法，其中所述反应在150℃至200℃下进行。
3.根据权利要求1或2所述的方法，其中所述反应在160℃至180℃下进行。
4.根据权利要求1至3中任一项所述的方法，其中所述反应在170℃下进行。
5.根据权利要求1至4中任一项所述的方法，其中铵盐选自溴化铵、三甲胺-HBr、三乙胺-HBr、吡啶-HBr、二甲基吡啶-HBr、溴化季铵盐、四烷基铵盐、四甲基溴化铵、四丙基溴化铵和四丁基溴化铵。
6.根据权利要求5所述的方法，其中铵盐为溴化铵。
7.根据权利要求1至6中任一项所述的方法，其中使用0.2至3当量的溴化铵盐。
8.根据权利要求1至7中任一项所述的方法，其中使用1当量的溴化铵盐。
9.根据权利要求1至8中任一项所述的方法，其中使用20至200当量的氨。
10.根据权利要求1至9中任一项所述的方法，其中使用40至100当量的氨。
11.根据权利要求1至10中任一项所述的方法，其中使用40至60当量的氨。
12.根据权利要求1至11中任一项所述的方法，其中，在反应结束后，将过量的氨直接冷凝至第二个高压釜中，然后在第二个高压釜中进行权利要求1至11所述的反应。
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