CN112218856A - 制备阿帕鲁胺的方法 - Google Patents
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- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 claims abstract description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 230000008569 process Effects 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- -1 silyl ester Chemical class 0.000 claims description 9
- 238000005804 alkylation reaction Methods 0.000 claims description 8
- 230000029936 alkylation Effects 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
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- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 6
- XOKAXPQJUODMSH-UHFFFAOYSA-N 4-amino-2-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(N)C=C1F XOKAXPQJUODMSH-UHFFFAOYSA-N 0.000 claims description 5
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
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- LJPCNSSTRWGCMZ-UHFFFAOYSA-N 3-methyloxolane Chemical compound CC1CCOC1 LJPCNSSTRWGCMZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
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- 239000000203 mixture Substances 0.000 description 15
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
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- 238000003786 synthesis reaction Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
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- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YREQYUFYDFSXJC-UHFFFAOYSA-N 1-bromocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1(Br)CCC1 YREQYUFYDFSXJC-UHFFFAOYSA-N 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical compound C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- FVTVMQPGKVHSEY-UHFFFAOYSA-N 1-AMINOCYCLOBUTANE CARBOXYLIC ACID Chemical compound OC(=O)C1(N)CCC1 FVTVMQPGKVHSEY-UHFFFAOYSA-N 0.000 description 1
- FGOGELABKVPEAL-UHFFFAOYSA-N 1-[3-fluoro-4-(methylcarbamoyl)anilino]cyclobutane-1-carboxylic acid Chemical compound C1=C(F)C(C(=O)NC)=CC=C1NC1(C(O)=O)CCC1 FGOGELABKVPEAL-UHFFFAOYSA-N 0.000 description 1
- JZFMNFJEQDUBPL-UHFFFAOYSA-N 1-sulfanyl-4,5-dihydroimidazole Chemical group SN1CCN=C1 JZFMNFJEQDUBPL-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
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- 238000005886 esterification reaction Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07C237/30—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 the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/24—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1896—Compounds having one or more Si-O-acyl linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及一种制备式(A)的阿帕鲁胺的方法。阿帕鲁胺是一种最新一代的雄激素受体抑制剂,用于治疗非转移性去势抵抗性前列腺癌。
Description
技术领域
本发明涉及制备下式的阿帕鲁胺(Apalutamide)的方法:
阿帕鲁胺是一种最新一代的雄激素受体抑制剂,用于治疗非转移性去势抵抗性前列腺癌。
现有技术
WO2007126765公开了通过使式V化合物
与下式化合物反应:
然后水解来合成阿帕鲁胺的方法。所述方法难以在工业上放大,因为它涉及在80℃下使用微波20小时。
WO2008119015和WO2011103202公开了阿帕鲁胺的合成方法,它们的特点都是大量的反应以及使用需要水解步骤的中间体,这降低了该方法的产率和经济性。
CN 108069869A描述了将4-卤代-2-氟-N-甲基苯甲酰胺用1-氨基环丁烷-1-甲酸烷基化生成4-[(1-羧基环丁基)氨基]-2-氟-N-甲基苯甲酰胺,然后按下面方案1中报道的方法酯化羧酸。
方案1
所得产物与化合物V反应得到阿帕鲁胺。
发明概述
现已发现了一种制备阿帕鲁胺的方法,其比已知方法更有利,因为该方法不需要危险的、难以控制的试剂(如氰化钾、硫光气等)或昂贵的催化剂,导致成本节约和较低的环境影响。
本发明方法的合成方案如下所示:
本发明的方法包括:
(a):将式I的4-氨基-2-氟-N-甲基苯甲酰胺
用式II的烷基卤进行烷基化
其中X是氯、溴或碘,优选溴,
得到式III化合物
(b):通过形成式IV化合物来活化式III化合物的羧基官能团
其中Y是羧基活化基团;
(c):将步骤(b)中得到的活化产物IV与式V的异硫氰酸酯缩合
得到阿帕鲁胺粗品;
(d):纯化步骤(c)中获得的阿帕鲁胺粗品。
第一步包括用烷基卤对胺进行烷基化,即,将中间体I,4-氨基-2-氟-N-甲基苯甲酰胺用中间体II,如1-溴环丁烷-1-甲酸进行烷基化。
所述烷基化是选择性的,并且不会导致形成源自多个连接的杂质和/或产生季铵盐。因此,反应产率和产物纯度没有受到损害,并且中间体III以晶体形式分离,具有良好的产率和非常高的纯度,不需要进一步纯化。
所述烷基化方法优于CN 108069869A(方案1)中公开的方法,后者包括使含有卤原子而不是氨基的中间体I与其中X是NH2的中间体II反应。
环丁烷环上的氨基的反应性不同于苯环上的氨基的反应性,并且芳基卤的除去容易性也不同于烷基卤的除去容易性。令人惊奇地发现,通过颠倒亲核氨基的位置,获得了与比较例中所示的产率的相当结果,但是该方法更适于工业应用。
本发明方法的步骤a)中的反应条件包括,仅使用7体积的溶剂而不是CN108069869A中所述的27体积,并且在60-65℃而不是100℃的温度下进行反应,反应小时数相等。
此外,本发明方法中所用的试剂4-氨基-2-氟-N-甲基苯甲酰胺I、1-溴环丁烷-1-甲酸II和5-异硫氰酸酯-3-(三氟甲基)-2-吡啶甲腈V是市售的。实施例1描述了该反应,以与CN 108069869A第7页第[0077]段所述相同的规模再现。
本发明方法的第二步包括中间体III的羧基官能团与能够形成稳定的活化羧酸衍生物IV的合适亲核试剂之间的缩合。优选的衍生物的实例是烷基酯、芳基酯、硫酯和甲硅烷基酯。所述酯的实例是中间体IVa、IVb、IVc和IVd。
所述酯可以被分离或不经分离而在随后的反应中“原样”使用。
本发明方法的第三步包括通过衍生物IV和中间体V之间的环化制备阿帕鲁胺。纯化并分离得到的粗品阿帕鲁胺(步骤d)。
式IVa、IVc和IVd的中间体是新的,并且是本发明的另一个目的。它们的使用是有利的,因为它不使用危险的和对环境有害的试剂。
本发明的方法具有在单一步骤中闭合硫代咪唑啉环的显著优点,不需要进一步官能化、水解成酰胺或去保护。
发明详述
步骤(a):4-氨基-2-氟-N-甲基苯甲酰胺I用1-溴环丁烷-1-甲酸II烷基化
该反应在碱存在下在极性非质子溶剂中,在20-100℃、优选40-80℃、最优选55-65℃的温度下进行。
反应可以使用二恶烷、四氢呋喃(THF)或3-甲基-四氢呋喃作为溶剂来进行,优选二恶烷。
碱可以是有机的或无机的,优选有机的。优选三乙胺。
反应在化合物II与化合物I的化学计量比为1-2、优选1.2-1.8、最优选1.4-1.6的条件下进行。
反应时间为10-40小时,优选20-30小时。
为了分离中间体III,将反应混合物在室温下冷却,得到沉淀。将得到的羧酸盐形式的产物溶解或悬浮在极性质子溶剂如水、甲醇或乙醇(优选水)中,并通过加入强酸如盐酸、氢溴酸或硫酸(优选盐酸)直至获得1.5至3.5,优选2至3的pH而转化为游离酸。产物沉淀并以高收率和高纯度分离得到游离酸。
步骤(b):中间体III的活化
中间体III优选活化为硫酯,如苄基硫酯IVa,烷基酯,如甲酯IVb,甲硅烷基酯,如三甲基甲硅烷基酯IVc,或芳基酯,如苯基酯IVd。
对于衍生为硫酯,可以使用二氯甲烷、甲苯或二甲基甲酰胺(DMF)作为溶剂,优选二氯甲烷。该反应可以用碱,优选二甲基氨基吡啶催化。衍生产物以晶体形式分离。
衍生成酯如甲酯IVb可以在溶剂如醇、二氯甲烷、甲苯、碳酸二甲酯(DMC)或二甲亚砜(DMSO)中进行,优选DMC或DMSO。
该反应可以用碱,优选碳酸钾催化。
衍生产物以晶体形式分离。
中间体III衍生为甲硅烷基酯(例如三甲基甲硅烷基酯IVc)在极性溶剂如二氯甲烷或二恶烷中进行,或者在无溶剂下进行,优选在甲硅烷基化试剂存在下在无溶剂条件下进行。
可用于制备三甲基甲硅烷基酯IVc的甲硅烷基化试剂的实例包括三甲基甲硅烷基氯、双(三甲基甲硅烷基)乙酰胺和六甲基二硅氮烷,优选六甲基二硅氮烷。反应在15-110℃、优选60-105℃、最优选90-100℃的温度下进行。
反应在甲硅烷基化剂与中间体III的化学计量比为1.5-10、优选3-9、最优选5-8的条件下进行。
当使用一些甲硅烷基化试剂时,必须使用酸如三氟乙酸、盐酸、氢溴酸等来活化反应,优选三氟乙酸;与其它甲硅烷基化试剂一起,必须使用碱如吡啶、三乙胺、二异丙胺等来中和形成的氢卤酸,优选吡啶。
反应时间为4-20小时、优选10-18小时、最优选12-16小时。在适当地改变溶剂后,产物可以以晶体形式分离。
中间体III也可衍生为芳基酯,例如衍生为苯基酯IVd;溶剂如二甲基乙酰胺、二甲基甲酰胺、二恶烷和二甲亚砜可用于所述衍生化,优选二甲亚砜,该反应可以用碱例如KHCO3、DBN、DBU、DMAP和TBD催化,优选DBN。反应在碱与中间体III的化学计量比为0.05-1当量、优选0.05-0.5、最优选0.1当量的条件下进行。反应在15-110℃、优选60-105℃、最优选90-100℃的温度下进行。反应时间为4-22小时、优选12-22小时、最优选15-20小时。
衍生产物以晶体形式分离。
步骤(c):中间体IVa-d和中间体V之间的偶联
反应在各种溶剂中进行,例如乙腈、乙酸乙酯、乙酸异丙酯、乙酸异丁酯、二甲亚砜、二甲基甲酰胺(DMF)等,优选二甲亚砜,最优选乙酸异丙酯和二甲亚砜的混合物。
反应在40-120℃、优选60-110℃、最优选80-100℃的温度下进行。
反应在中间体IVa-d与中间体V的化学计量比为1-2、优选1.2-1.8、最优选1.3-1.6的条件下进行。
反应时间为10-60小时、优选15-40小时、最优选20-30小时。
在适当的后处理之后,可以通过结晶或其它已知技术纯化阿帕鲁胺粗产物。
现在将通过以下实施例进一步说明该方法。
实施例1:中间体III的合成
将化合物I(20g,0.119mol)悬浮于140mL二恶烷中。通过倾泻成细流加入TEA(50mL,0.359mol)。将该体系置于氮气下,并加热至60℃。单独制备中间体II(32g,0.179mol)在60mL二恶烷中的溶液。
将化合物II的溶液加入到反应器中的悬浮液中,并使其反应约20小时。然后将混合物冷却至15℃,通过布氏漏斗过滤,每次用20mL二恶烷洗涤滤饼两次。将所得产物悬浮于240mL水中,加入1M HCl直至pH<3,然后将所得悬浮液通过布氏漏斗过滤,每次用40mL水洗涤滤饼两次。
将由此分离的晶体在60℃的温度下真空干燥,以65%的产率(20.5g,77.3mmol)和99.6%的HPLC纯度得到中间体III。
1H NMR(300MHz,CDCl3)δ15.3(m,4H),2.58(t,br,2H),2.73(s,3H),6.00(m,1H),6.22(s,1H),7.17(s,1H),7.46(s,1H),7.65(d,1H),12.63(m,1H)。
实施例2:中间体IVa的合成
将中间体III(20g,75mmol)悬浮于120mL二氯甲烷中并冷却至0-5℃。当达到所述温度时,通过倾泻成细流加入苄基硫醇(12.6mL,106.7mmol),确保温度不超过5℃。
单独制备二环己基碳二亚胺(DCC)(17g,82.4mmol)在40mL二氯甲烷中的溶液。然后将形成的DCC溶液滴加到中间体III的悬浮液中,确保温度不超过7℃。滴加结束时,加入DMAP(145mg,1.2mmol),将混合物加热到20-25℃,并使其反应约17小时。在不超过30℃的条件下,加入130mL水和100mL 14重量%的次氯酸钠溶液,搅拌混合物8小时。
将得到的两相混合物通过布氏漏斗过滤,将滤饼用二氯甲烷洗涤两次,每次20mL;可以丢弃固体。分离各相,有机相用水洗涤三次,每次160mL。
所得有机相用甲苯进行溶剂交换;形成大量沉淀,并将其缓慢冷却过夜。通过布氏漏斗过滤沉淀,用30mL甲苯洗涤滤饼。将由此分离的晶体在60℃的温度下真空干燥,以78%的收率(22g,59mmol)和95%的HPLC纯度得到中间体IVa。
1H NMR(300MHz,CDCl3)δ1.80-2.25(m,4H),2.56(m,2H),2.72(d,3H),4.02(s,2H),6.00-6.20(dd,2H),7.27(m,5H),7.50(m,2H),7.16(t,br,1H)。
实施例3:中间体IVb的合成
将中间体III(20g,75mmol)溶于200mL DMSO,加入碳酸二甲酯(50mL,594mmol)和碳酸钾(4.15g,30mmol);将该体系置于氮气下并在90℃下加热22小时,然后冷却至室温,加入200mL二氯甲烷和250mL水,将混合物搅拌10分钟,分离各相。水相用100mL二氯甲烷萃取。合并的有机相用250mL水洗涤,浓缩至残余物;向残余物中加入100mL甲苯并在50℃下搅拌30分钟,然后在室温下搅拌1小时。将固体通过布氏漏斗过滤,用50mL甲苯洗涤滤饼。
将所得晶体在60℃的温度下真空干燥,以92%的产率(19.5g,69.5mmol)和>99.9%的HPLC纯度得到中间体IVb。
1H NMR(300MHz,CDCl3)1.80-2.25(m,4H),2.60(m,2H),2.70(d,3H),3.60(s,3H),5.95-6.21(dd,2H),7.23(s,1H),7.44(t,1H),7.63(t,br1H)。
实施例4:中间体IVc的合成
将中间体III(30g,112.6mmol)悬浮于HMDS(150mL,715.6mmol)并置于氮气下。在15分钟内将TFA(2mL,25.9mmol)滴入悬浮液中,确保温度不超过30℃。将反应物料加热至回流(约130℃)4小时,随后用甲苯进行溶剂交换;观察到大量的晶体沉淀。将混合物缓慢冷却过夜,然后通过布氏漏斗过滤,用30mL甲苯洗涤滤饼。将所得晶体在50℃的温度下真空干燥,以85%的产率得到中间体IVc(32.3g,95.7mmol)。
实施例5:中间体IVd的合成
将中间体III(50g,187.8mmol)、碳酸二苯酯(48.2g,225.0mmol)和DBN(2.3mL)悬浮于5体积DMSO中并置于氮气下。
将反应物料在90℃下加热20小时。降温至20℃,加水,使产物沉淀。通过布氏漏斗过滤沉淀,用水洗涤滤饼。
向湿产物中加入10体积的甲苯并在氮气下于室温搅拌至少6小时。通过布氏漏斗过滤产物,用甲苯洗涤滤饼。
将所得晶体在50℃的温度下真空干燥,以87%的产率得到中间体IVd(56.3g,164.1mmol)。
1H NMR(300MHz,CDCl3)1.95-2.42(m,4H),2.80(m,2H),2.74(d,3H),6.16-6.33(dd,2H),6.94(d,2H),7.26(t,1H),7.40(m,3H),7.55(t,1H),7.70(t,br,1H)。
实施例6:阿帕鲁胺的合成
将中间体IVa-d(40.3mmol)和中间体V(12g,52.3mmol)溶于乙酸异丙酯(15mL)和DMSO(7.5mL)的混合物中。将混合物置于氮气下并加热至回流(约90℃)约17小时。将反应物冷却至60℃,加入67mL乙酸异丙酯。有机相用150mL的5%重量的NaCl水溶液洗涤两次,用150mL水洗涤一次。然后通过乙酸异丙酯的连续蒸馏干燥有机相,将其减少至22.5mL的剩余体积。
在旋转蒸发器中将有机相浓缩至残余物并将产物通过硅胶柱色谱纯化,用己烷/异丙醇(7:3)作为洗脱剂。
以30-35%的产率和80%的HPLC纯度分离出产物。
1H NMR(300MHz,CDCl3)δ1.73(m,1H),2.28(m,1H),2.50-2.80(m,4H),3.07(d,3H),6.73(m,1H),7.13-7.29(dd,2H),8.28-8.38(dd,2H),9.08(d,1H)。
实施例7:中间体III的合成
将化合物I(100g,0.594mol)悬浮于300mL二恶烷中。通过倾泻成细流加入TEA(250mL,3.59mol)。将该体系置于氮气下,并加热至60℃。单独制备中间体II(160g,0.90mol)在150mL二恶烷中的溶液。
将化合物II的溶液加入到反应器中的悬浮液中,并使其反应约20小时。将混合物冷却至15℃,通过布氏漏斗过滤,每次用100mL二恶烷洗涤滤饼两次。将所得产物悬浮于1200mL水中,加入1M HCl直至pH<3,然后将所得悬浮液通过布氏漏斗过滤,每次用200mL水洗涤滤饼两次。
将由此分离的晶体在60℃的温度下真空干燥,以76%的产率(120g,45.1mmol)和99.6%的HPLC纯度得到中间体III。
1H NMR(300MHz,CDCl3)δ15.3(m,4H),2.58(t,br,2H),2.73(s,3H),6.00(m,1H),6.22(s,1H),7.17(s,1H),7.46(s,1H),7.65(d,1H),12.63(m,1H)。
实施例8:中间体IVd的合成
将中间体III(50g,187.8mmol)、碳酸二苯酯(48.2g,225.0mmol)和DBN(2.3mL)悬浮于5体积DMSO中并置于氮气下。
将反应物料在65℃下加热至少20小时。将温度降低至20℃,加入水和丙酮的混合物,使产物沉淀。将混合物搅拌直至形成大量沉淀,通过布氏漏斗过滤,用水洗涤滤饼。
向湿产物中加入10体积碳酸二甲酯/环己烷的8/2混合物,并在氮气下在室温下搅拌至少6小时。将混合物通过布氏漏斗过滤,用环己烷洗涤滤饼。
将所得晶体在50℃的温度下真空干燥,以87%的产率得到中间体IVd(56g,163.3mmol)。
1H NMR(300MHz,CDCl3)1.95-2.42(m,4H),2.80(m,2H),2.74(d,3H),6.16-6.33(dd,2H),6.94(d,2H),7.26(t,1H),7.40(m,3H),7.55(t,1H),7.70(t,br,1H)。
实施例9:阿帕鲁胺的合成
将中间体IVa-d(146mmol)和中间体V(67g,292mmol)溶于乙酸异丙酯(150mL)和DMSO(5.2mL)的混合物中。将混合物置于氮气下并加热至回流(约90℃)约17小时。将反应物料冷却至60℃并从合适的有机溶剂中结晶,得到65-68g粗品阿帕鲁胺,其经适当重结晶得到50-52g纯度超过99%的阿帕鲁胺,产率72-73%。
1H NMR(300MHz,CDCl3)δ1.73(m,1H),2.28(m,1H),2.50-2.80(m,4H),3.07(d,3H),6.73(m,1H),7.13-7.29(dd,2H),8.28-8.38(dd,2H),9.08(d,1H)。
Claims (8)
2.根据权利要求1所述的方法,其中步骤(a)在二恶烷、四氢呋喃或3-甲基-四氢呋喃中进行。
3.根据权利要求2所述的方法,其中步骤(a)在二恶烷中进行。
4.根据权利要求1或2所述的方法,其中在步骤(b)中将中间体III转化为硫酯、烷基酯、甲硅烷基酯或芳基酯。
6.根据权利要求4或5所述的方法,其中步骤(b)在选自醇、二氯甲烷、甲苯、碳酸二甲酯和二甲亚砜的溶剂中进行,优选碳酸二甲酯或二甲亚砜。
7.根据权利要求1至6中一项或多项所述的方法,其中步骤(c)在选自乙腈、乙酸乙酯、乙酸异丙酯、乙酸异丁酯、二甲亚砜和二甲基甲酰胺的溶剂中进行。
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US10513504B2 (en) * | 2018-03-08 | 2019-12-24 | Apotex Inc. | Processes for the preparation of apalutamide and intermediates thereof |
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2018
- 2018-05-30 IT IT102018000005874A patent/IT201800005874A1/it unknown
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2019
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- 2019-05-27 EP EP19735634.8A patent/EP3802515B1/en active Active
- 2019-05-27 US US17/059,551 patent/US11820752B2/en active Active
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US20150094296A1 (en) * | 2012-03-28 | 2015-04-02 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US20160229814A1 (en) * | 2013-03-14 | 2016-08-11 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US20180141914A1 (en) * | 2015-05-28 | 2018-05-24 | Olon S.P.A. | Process for the preparation of enzalutamide |
WO2018014802A1 (en) * | 2016-07-18 | 2018-01-25 | National Institute Of Biological Sciences, Beijing | Apoptosis inhibitors |
CN108069869A (zh) * | 2016-11-09 | 2018-05-25 | 上海医药工业研究院 | 一种Apalutamide的制备方法及其中间体 |
CN107501237A (zh) * | 2017-08-17 | 2017-12-22 | 上海西浦医药科技有限公司 | 一种Apalutamide的合成新方法 |
CN108047200A (zh) * | 2017-12-05 | 2018-05-18 | 上海丰瑞医药科技有限公司 | 一种二芳基乙内酰硫脲类化合物的制备方法及其中间体 |
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IT201800005874A1 (it) | 2019-11-30 |
US11820752B2 (en) | 2023-11-21 |
EP3802515A1 (en) | 2021-04-14 |
US20210206742A1 (en) | 2021-07-08 |
CA3100162A1 (en) | 2019-12-05 |
ES2946905T3 (es) | 2023-07-28 |
WO2019229625A1 (en) | 2019-12-05 |
EP3802515B1 (en) | 2023-05-10 |
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