CN114478631A - 福沙匹坦二甲葡胺的制备 - Google Patents
福沙匹坦二甲葡胺的制备 Download PDFInfo
- Publication number
- CN114478631A CN114478631A CN202210211066.XA CN202210211066A CN114478631A CN 114478631 A CN114478631 A CN 114478631A CN 202210211066 A CN202210211066 A CN 202210211066A CN 114478631 A CN114478631 A CN 114478631A
- Authority
- CN
- China
- Prior art keywords
- bis
- fosaprepitant
- reaction
- process according
- diester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940044880 fosaprepitant dimeglumine Drugs 0.000 title description 15
- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NN(P(O)(O)=O)C(=O)N1 VRQHBYGYXDWZDL-OOZCZQCLSA-N 0.000 title description 15
- 238000002360 preparation method Methods 0.000 title description 6
- 229960002891 fosaprepitant Drugs 0.000 claims abstract description 20
- -1 fosaprepitant diester Chemical class 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 7
- LTCTZTUBZBGWMR-UHFFFAOYSA-N OCC(NC1=O)=NN1OP(O)=O Chemical compound OCC(NC1=O)=NN1OP(O)=O LTCTZTUBZBGWMR-UHFFFAOYSA-N 0.000 claims abstract description 5
- AFBDSAJOMZYQAI-CNOZUTPLSA-N (2s,3r)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine Chemical compound C1([C@@H]2NCCO[C@@H]2O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=CC=C(F)C=C1 AFBDSAJOMZYQAI-CNOZUTPLSA-N 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000010189 synthetic method Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- LAXRNWSASWOFOT-UHFFFAOYSA-J (cymene)ruthenium dichloride dimer Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Ru+2].[Ru+2].CC(C)C1=CC=C(C)C=C1.CC(C)C1=CC=C(C)C=C1 LAXRNWSASWOFOT-UHFFFAOYSA-J 0.000 claims description 2
- UAXNXOMKCGKNCI-UHFFFAOYSA-N 1-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 UAXNXOMKCGKNCI-UHFFFAOYSA-N 0.000 claims description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 2
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 claims description 2
- QMPSUPWBJMOGPS-UHFFFAOYSA-N [Ru].CC(C)C1=CC=C(C)C=C1 Chemical compound [Ru].CC(C)C1=CC=C(C)C=C1 QMPSUPWBJMOGPS-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 231100000024 genotoxic Toxicity 0.000 description 13
- 230000001738 genotoxic effect Effects 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 8
- 229960001372 aprepitant Drugs 0.000 description 8
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 206010047700 Vomiting Diseases 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 4
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 4
- DWCCMKXSGCKMJF-YNXGUESPSA-N (2r,3s)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine;hydrochloride Chemical compound Cl.C1([C@@H]2NCCO[C@@H]2O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=CC=C(F)C=C1 DWCCMKXSGCKMJF-YNXGUESPSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 3
- 102100024304 Protachykinin-1 Human genes 0.000 description 3
- 230000003474 anti-emetic effect Effects 0.000 description 3
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 1
- ZLRBJVJEQXBAAI-UHFFFAOYSA-N 5-(chloromethyl)-1,2-dihydro-1,2,4-triazol-3-one Chemical compound ClCC1=NC(=O)NN1 ZLRBJVJEQXBAAI-UHFFFAOYSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002246 antineoplastic agent 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
- 230000000903 blocking effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- NSBNXCZCLRBQTA-UHFFFAOYSA-N dibenzyl bis(phenylmethoxy)phosphoryl phosphate Chemical compound C=1C=CC=CC=1COP(OP(=O)(OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)(=O)OCC1=CC=CC=C1 NSBNXCZCLRBQTA-UHFFFAOYSA-N 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
本发明涉及一条制备福沙匹坦双酯的合成方法，具体为(2R,3S)‑2‑((R)‑1‑(3,5‑双(三氟甲基)苯基)乙氧基)‑3‑(4‑氟苯基)吗啉在催化剂和配体的作用下与(3‑(羟甲基)‑5‑氧代‑4,5‑二氢‑1H‑1,2,4‑三唑‑1‑基)膦酸酯下发生缩合反应，制备得到福沙匹坦双酯。
Description
技术领域
本发明涉及化学合成领域，涉及制备福沙匹坦的方法。
背景技术
福沙匹坦二甲葡胺是一种NK-1选择性、高亲和性受体拮抗剂，为国内外指南一致推荐用于高度、中度致吐性化疗方案(HEC/MEC)的止吐药物，主要通过阻断大脑恶心和呕吐信号作用机制发挥作用，用于预防化疗相关性恶心呕吐，可与5-HT3受体拮抗剂合用以提高止吐效力。作为注射剂型，该药物能够满足临床上不能口服、吞咽困难或消化功能低下的患者，可以让更广泛人群获益。临床研究显示，福沙匹坦(商品名：坦能)能有效预防化疗相关性恶心呕吐，具备良好的临床应用安全性，坦能单日单次注射使用具有剂量准确、起效迅速、方便快捷等特点。这种药物是一种神经激肽-1(NK-1)受体拮抗剂，是阿瑞匹坦的前体药物，临床用于预防化疗药引起的恶心和呕吐。该产品为静脉注射用粉针剂，安全性较高，临床使用广泛。相较于口服阿瑞匹坦，对于一些有与疾病相关恶心无法接受口服给药的患者，使用注射给药能够提供更大的灵活性和便利性。该产品已成为治疗肿瘤的处方组合必备的止吐药。
福沙匹坦二甲葡胺作为阿瑞匹坦的前药(Prodrug)，具有和阿瑞匹坦相同的临床疗效，美国FDA和欧洲EMA于2008年1月批准了福沙匹坦的上市申请，作为化疗的辅助用药，防止化疗引起的恶心、呕吐等。有专利和文献报道，福沙匹坦的一条合成路线是从(2R,3S)-2-((R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉盐酸盐出发，首先和2-(2-氯-1-亚乙基)酰肼甲酸甲酯发生亲核取代反应，随后关环得到阿瑞匹坦。然后阿瑞匹坦和焦磷酸四苄酯反应制备得到福沙匹坦双苄酯，福沙匹坦双苄酯经过氢化去除苄基保护同时得到的游离碱和二甲葡胺成盐制备得到福沙匹坦二甲葡胺。另外，专利和文献(WO01/94324；JACS,2003,2129-2135etc)还报道了另外一条从(2R,3S)-2-((R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉盐酸盐出发制备阿瑞匹坦的路线，具体涉及该盐酸盐和5-氯甲基-2,4-二氢[1,2,4]三唑-3-酮缩合。阿瑞匹坦、福沙匹坦二甲葡胺的结构以及上述合成路线如下：
专利CN104650143报道了合成福沙匹坦双苄酯的合成。该合成涉及(2R,3S)-2-((R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉盐酸盐和(3-(氯甲基)-5-氧代-4,5-二氢-1H-1,2,4-三唑-1-基)膦酸二苄酯反应，制备得到福沙匹坦双苄酯。相关合成路线如下：
上述的合成福沙匹坦二甲葡胺的合成路线都涉及到中间体福沙匹坦双苄酯，且合成福沙匹坦双苄酯的合成路线都涉及到相关的氯甲基化合物，由于氯甲基化合物归属于基因毒性化合物和潜在的基因毒性化合物，且由于福沙匹坦二甲葡胺是注射剂品种对于基因毒性化合物和潜在基毒化合物的残留要求高(基于TTC法和福沙匹坦二甲葡胺日用量计算，这些基毒杂质和潜在基毒杂质单个的残留量应低于130ppm)，因此，这些基毒杂质基因毒性化合物和潜在的基因毒性化合物的使用和去除对于福沙匹坦二甲葡胺的产业化是一个巨大的挑战。上述合成路线涉及使用的基因毒性化合物和潜在的基因毒性化合物的结构如下：
发明内容
本发明所要解决的技术问题在于提供一条新的制备福沙匹坦双酯的合成方法，该方法可以规避氯甲基类基因毒性化合物的使用。
研究发现，(2R,3S)-2-((R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉(化合物式II)在催化剂和配体的作用下与(3-(羟甲基)-5-氧代-4,5-二氢-1H-1,2,4-三唑-1-基)膦酸酯(化合物式I)发生缩合反应，可以制备得到福沙匹坦双酯(化合物式III),具体反应式如下：
反应所使用催化剂为[Ru(p-cymene)Cl2]2(二氯双(4-甲基异丙苯)钌(II))；
反应所使用的配体为双膦配体，选自双(2-二苯基膦苯基)醚，1,1'-双(二苯基膦)二茂铁、[1,1'-联萘]-2,2'-双二苯膦，1,4-双(二苯基膦)丁烷，双二苯基膦乙烷，1,4-双(二苯基膦)烷；
反应所使用的溶剂为甲苯，乙腈，二甲苯；
化合物式I中R为H，Me；
化合物式III中R为H，Me；
该路线由于不涉及使用氯甲基类化合物进行福沙匹坦双酯的制备，规避了基因毒性化合物和潜在基因毒性化合物的使用，对于最终产品福沙匹坦二甲葡胺的质量提升具有重要意义。
具体实施方式
通过下面的实施例可以更具体的理解本发明，但其是举例说明而不是限制本发明的范围。
实施例
1、制备福沙匹坦双酯(化合物式III，R＝H)
200mL反应瓶,配备磁力搅拌和回流装置，氮气保护下依次加入催化剂[Ru(p-cymene)Cl2]2(400mg,0.653mmol)和1,1'-双(二苯基膦)二茂铁(700mg,1.263mmol)。然后氮气保护下加入(3-(羟甲基)-5-氧代-4,5-二氢-1H-1,2,4-三唑-1-基)膦酸酯(化合物式I,R＝H)(18.77g,50.01mmol)、(2R,3S)-2-((R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉(化合物式II)(21.88g,50.03mmol)和无水甲苯(70mL),加入完毕后，体系再次使用氮气置换3次。随后，反应体系缓慢加热至回流反应24小时。反应体系降温至室温，体系旋转蒸发仪减压脱除溶剂，残余物柱层析纯化得福沙匹坦双酯(化合物式III，R＝H)(36.56g,92％)。1H NMR(600MHz，DMSO)：δ(ppm)：12.02(s,1H),7.85(s,1H),7.49(s,2H),7.32～7.37(m,12H),7.06(t,J＝6.0Hz,2H),5.12～5.19(m,4H),4.95(q,J＝6.0Hz,1H),4.33(d,J＝3.0Hz,1H),4.11(td,J＝12.0,1.2Hz,1H),3.63(dd,J＝10.8,1.2Hz,1H),3.51(d,J＝2.4Hz,1H),3.37(s,1H),2.79～2.81(m,2H),2.40(td,J＝11.4,3.0Hz,1H),1.36(s,3H)。
2、制备福沙匹坦双酯(化合物式III，R＝Me)
25mL反应瓶，氮气保护下依次加入催化剂[Ru(p-cymene)Cl2]2(80mg,0.131mmol)和[1,1'-联萘]-2,2'-双二苯膦(160mg,0.257mmol)、(3-(羟甲基)-5-氧代-4,5-二氢-1H-1,2,4-三唑-1-基)膦酸酯(化合物式I,R＝Me)(4.05g,10.04mmol)、(2R,3S)-2-((R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉(化合物式II)(4.40g,10.06mmol)和无水二甲苯(12mL),加入完毕后，体系再次使用氮气置换3次。随后，反应体系缓慢加热至110±5℃反应24小时。反应体系降温至室温，体系旋转蒸发仪减压脱除溶剂，残余物柱层析纯化得福沙匹坦双酯(化合物式III，R＝Me)(6.99g,84.6％)。
3、制备福沙匹坦二甲葡胺
100mL高压反应瓶中依次加入实施例1制备得到的福沙匹坦双酯(化合物式III,R＝H)(5.0g,6.29mmol)、葡甲胺(2.8g,14.47mmol)、甲醇(30.0g)和钯碳(0.5g，含钯10％)，搅拌均匀，体系用氮气置换三次，再用氢气置换三次。随后反应体系保持25±5℃、氢气压力0.2～0.3MPa搅拌反应24h。反应液过滤，体系旋转蒸发仪减压脱除溶剂，残余物加入甲醇(50.0g)溶解，缓慢滴加丙酮(200.0g)，固体析出，过滤后干燥，得到福沙匹坦二甲葡胺(5.14g,81.3％)。
Claims (6)
1.一条制备福沙匹坦双酯的合成方法，具体为(2R,3S)-2-((R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉(化合物式II)在催化剂和配体的作用下与(3-(羟甲基)-5-氧代-4,5-二氢-1H-1,2,4-三唑-1-基)膦酸酯(化合物式I)发生缩合反应，制备得到福沙匹坦双酯(化合物式III),具体反应式如下：
2.如权利要求1所述的制备方法，反应所使用催化剂为[Ru(p-cymene)Cl2]2(二氯双(4-甲基异丙苯)钌(II))。
3.如权利要求1所述的制备方法，反应所使用的配体为双膦配体，选自双(2-二苯基膦苯基)醚，1,1'-双(二苯基膦)二茂铁、[1,1'-联萘]-2,2'-双二苯膦，1,4-双(二苯基膦)丁烷，双二苯基膦乙烷，1,4-双(二苯基膦)烷。
4.如权利要求1所述的制备方法，反应所使用的溶剂为甲苯，乙腈，二甲苯。
5.如权利要求1所述的制备方法，式I所示的化合物中R为H，Me。
6.如权利要求1所述的制备方法，式III所示的化合物中R为H，Me。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210211066.XA CN114478631A (zh) | 2022-03-03 | 2022-03-03 | 福沙匹坦二甲葡胺的制备 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210211066.XA CN114478631A (zh) | 2022-03-03 | 2022-03-03 | 福沙匹坦二甲葡胺的制备 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114478631A true CN114478631A (zh) | 2022-05-13 |
Family
ID=81487014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210211066.XA Pending CN114478631A (zh) | 2022-03-03 | 2022-03-03 | 福沙匹坦二甲葡胺的制备 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114478631A (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650143A (zh) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | 制备福沙匹坦二甲葡胺中间体的方法 |
| CN104650142A (zh) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | 一种福沙匹坦二甲葡胺的制备方法 |
| CN113582982A (zh) * | 2021-06-15 | 2021-11-02 | 山东罗欣药业集团股份有限公司 | 一种nk1受体拮抗剂的制备方法 |
-
2022
- 2022-03-03 CN CN202210211066.XA patent/CN114478631A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650143A (zh) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | 制备福沙匹坦二甲葡胺中间体的方法 |
| CN104650142A (zh) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | 一种福沙匹坦二甲葡胺的制备方法 |
| CN113582982A (zh) * | 2021-06-15 | 2021-11-02 | 山东罗欣药业集团股份有限公司 | 一种nk1受体拮抗剂的制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| M. HANITI S. A. HAMID等: "Ruthenium-Catalyzed N-Alkylation of Amines and Sulfonamides Using Borrowing Hydrogen Methodology", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》, vol. 131, no. 5, pages 1766 - 1774 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU677644B2 (en) | Piperazine derivatives | |
| KR100812046B1 (ko) | 1-(2ｓ,3ｓ)-2-벤즈히드릴-ｎ-(5-삼급-부틸-2-메톡시벤질)퀴누클리딘-3-아민의 제조 방법 | |
| JP2002531457A (ja) | 架橋テトラアザマクロサイクル類の製造方法 | |
| EP0604181A1 (en) | Antitumor compositions and method of treatment | |
| TW385247B (en) | Aromatic acetylcholinesterase inhibitors | |
| EP3067353B1 (en) | A process for the preparation of solifenacin salts and their inclusion into pharmaceutical dosage forms | |
| CA1288102C (en) | Pyridine derivatives, their preparation and their use | |
| CN114478631A (zh) | 福沙匹坦二甲葡胺的制备 | |
| JPH01151571A (ja) | 新規な抗高血圧性ベンゾピラン誘導体 | |
| US4379160A (en) | Carbazole compounds and medicinal use thereof | |
| JP2001521035A (ja) | ３−置換テトラヒドロピリドピリミジノン−誘導体、その製造方法及びその使用 | |
| JP2008538746A (ja) | ヒドロコドン、ヒドロモルホンおよびその誘導体の触媒的製造方法 | |
| DE3101502A1 (de) | Phenylpiperazinderivate von hetarylphenolen und hetarylanilinen, ihre hersttellung und diese enthaltendetherapeutische mittel | |
| IE911184A1 (en) | New ethylene-substituted¹phenylalkylethylenediamine-platinum(ii oriv) derivatives and¹phenylalkylethylenediamines | |
| CN114853658A (zh) | 一种以咔唑和对溴苯酚原料的9-(4-溴苯基)咔唑的合成方法 | |
| IE51889B1 (en) | (hetarylphenoxy)-(phenylpiperazinyl)-propanols,their preparation and drugs containing these compounds | |
| CS205050B2 (en) | Method of preparing 4-/7-brom-5-methoxy-2-benzofuranyl/-1-methylpiperidine | |
| WO2022011948A1 (zh) | 制备沃替西汀的方法 | |
| CN101558073A (zh) | 制备高纯度4a,5,9,10,11,12,-六氢-6H-苯并呋喃并[3a,3,2-ef][2]苯并氮杂䓬及其衍生物的方法 | |
| BRPI0921632B1 (pt) | Processo para preparar nebivolol | |
| JPH11505809A (ja) | 新規のキノキサリンジオン誘導体、その製造および薬剤への応用 | |
| JPH06508112A (ja) | アミノアルキル置換された５−メルカプトチアゾール、その製造及び使用 | |
| RU2639150C2 (ru) | Способ получения производного эндо-9-азабицикло[3.3.1]нонан-3-ола | |
| JPH06508113A (ja) | アミノアルキル置換されたチアゾリン−２−オン、その製造及び使用 | |
| CN109485613B (zh) | 阿瑞匹坦和福沙匹坦边链片段的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |