CN108884048B - 一种吡啶酮类衍生物的制备方法及其中间体 - Google Patents
一种吡啶酮类衍生物的制备方法及其中间体 Download PDFInfo
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- CN108884048B CN108884048B CN201780020531.9A CN201780020531A CN108884048B CN 108884048 B CN108884048 B CN 108884048B CN 201780020531 A CN201780020531 A CN 201780020531A CN 108884048 B CN108884048 B CN 108884048B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 67
- 230000008569 process Effects 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 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 12
- 150000007524 organic acids Chemical class 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 3
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 3
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- FJCRIRSBTDHYIW-UHFFFAOYSA-N FC1=C(C=CC(=C1)[N+](=O)[O-])NC=1N(C(C=C(C=1C(=O)N)OC=1C=NC(=CC=1)C)=C=O)C Chemical compound FC1=C(C=CC(=C1)[N+](=O)[O-])NC=1N(C(C=C(C=1C(=O)N)OC=1C=NC(=CC=1)C)=C=O)C FJCRIRSBTDHYIW-UHFFFAOYSA-N 0.000 description 5
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- KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 4
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
- C07D213/78—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
- C07D213/82—Amides; Imides in position 3
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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Abstract
本发明涉及一种吡啶酮类衍生物的制备方法及其中间体。具体地,本发明涉及一种由式(6)所示化合物制备得到式(II)所示吡啶酮类衍生物、其可药用盐的制备方法和制备过程中的中间体及其制备方法。
Description
技术领域
本发明涉及一种吡啶酮类衍生物、其可药用盐的制备方法和制备过程中的中间体及其制备方法,该吡啶酮类衍生物、其可药用盐及含有该衍生物的药物组合物作为MEK抑制剂用于制备治疗癌症药物中的用途。
背景技术
丝/苏氨酸促分裂原活化蛋白激酶(MAPKs,也称胞外信号调节激酶,ERKs)由酪氨酸激酶受体(如EGF受体)和/或G蛋白异源三聚体相关的细胞因子受体激活,可与多种由不同第二信使激起的胞内信号相互作用,磷酸化和调节各种酶及转录因子的活性(如NF-κB,Rsk90,磷脂酶A2,c-Myc,CREB,Ets-1,AP-1及c-jun等)。MEKs也称MAP激酶(MAPKK或Erk激酶),属于双特异性激酶,可磷酸化MAPK(p44MAPK(Erk1)及p42MAPK(Erk2)的丝/苏氨酸残基和酪氨酸残基(Erk1磷酸化位点为T202和Y204,Erk2磷酸化位点为T183和Y185),MEK家族包含五种基因:MEK1,MEK2,MEK3,MEK4和MEK5。MEKs的N-端为负调控区,C-端的催化区具有与Erks结合并激活Erks的功能,实验发现,敲除MEK1的调控区会导致MEK1和Erk固有活性的抑制。
针对MAPK信号通路,目前已有多个特异性抑制Raf和MEK活性的化合物处于临床和上市阶段。其中sorafenib(Bay43-9006)于2006年上市,属非特异性的丝/苏氨酸和酪氨酸激酶抑制剂,其作用靶点包含Raf,MEK,VEGFR2/3,Flt-3,PDGFR,c-Kit等。B-Raf特异性抑制剂如dabrafenib(GSK2118436)和vemurafenib(PLX4032)显示良好的临床效果,但持续时间并不长久,同时,临床研究发现,接受PLX4032有效治疗的患者,其症状大部分复发,提示B-Raf抑制剂的长期治疗会导致患者产生获得性耐药性,对B-Raf抑制剂不再敏感。为克服患者的耐药性,临床上常将MEK抑制剂与B-Raf抑制剂联用。特异性抑制MEK1/2抑制剂Trametinib(GSK-1120212)由GSK公司开发,现已进入预注册阶段,其它MEK1/2抑制剂Selumetinib(AZD-6422),Pimasertib hydrochloride(AS-703026),TAK-733等已进入临床试验阶段,但这些MEK抑制剂并无公布其与Erk1或Erk2的相互作用数据。
目前公开了一系列的MEK抑制剂的专利申请,其中包括WO2007096259、WO2010003022和WO2012162293等。
专利申请WO2015058589A1(公开日2015.04.30)中公开了一种结构新型的高效低毒的针对MAPKs信号通路的抑制剂,特别是CYP450抑制作用小、活性高、优异的抗肿瘤细胞增殖作用的MEK靶点抑制剂,结构如下式(II)所示:
WO2015058589A1(公开日2015.04.30)的实施例1和实施例31公开了化合物31的制备方法,总计十一步反应,具体反应如下所示:
该方法最终通过制备分离法纯化得到目标产物,产率为30.3%,该方法存在反应步数较多、反应时间较长、存在高温反应(第七步反应温度为230℃)、产率低等问题,不利于工业扩大生产。
发明内容
本发明要解决的技术问题是提供一种与现有技术完全不相同的制备式(II)所示化合物的方法,改变起始原料和中间体制备目标产物,通过缩短反应步骤、起始原料等反应物简单易购买、反应条件简单可控、避免高温反应、反应后处理方法简单等途径优化制备方法,提高产率、利于工业扩大生产。
本发明的技术方案如下:
本发明提供一种制备通式(II)所示化合物的方法,其特征在于,所述方法为由式(6)化合物制备式(II)所示化合物,
其中,
Ra、Rb选自氢原子、卤素、C1-6烷基或卤代C1-6烷基;
R1选自任选取代的苯基或吡啶基,所述取代基选自C1-6烷基、卤素、卤代C1-6烷基、C1-6烷氧基、C1-6烷基氨基羰基、C1-6烷基羰基氨基、3-14元杂环基氧基、3-14元环烷基氨基羰基、3-14元环烷基羰基氨基或C1-6烷基磺酰氨基,3-14元杂环基优选为3-8元杂环基,3-14元环烷基优选为3-8元环烷基;
R2选自氢原子、卤素或任选取代的C1-6烷基,所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基,3-14元环烷基优选为3-8元环烷基,3-14元杂环基优选为3-8元杂环基,6-14元芳基优选为6-8元芳基,5-15元杂芳基优选为5-8元杂芳基。
在本发明的一个优选实施例方案中,本发明提供一种制备通式(II)所示化合物的方法,其特征在于,所述方法还包括由式(5)化合物制备式(6)化合物,
在本发明的一个优选实施例方案中,本发明提供一种制备通式(II)所示化合物的方法,其特征在于,所述方法还包括由式(4)化合物制备式(5)化合物,
在本发明的一个优选实施例方案中,本发明提供一种制备通式(II)所示化合物的方法,其特征在于,所述方法还包括由式(3)化合物制备式(4)化合物,
在本发明的一个优选实施例方案中,本发明提供一种制备通式(II)所示化合物的方法,其特征在于,所述方法还包括由式(2)化合物制备式(3)化合物,
在本发明的一个优选实施例方案中,本发明提供一种制备通式(II)所示化合物的方法,其特征在于,所述方法还包括由式(1)化合物制备式(2)化合物,
本发明进一步涉及一种化合物如式(6)所示,
其中,Ra、R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(6)所示化合物的方法,其特征在于,所述方法包括由式(5)化合物制备式(6)化合物,
本发明的另一方面涉及一种制备通式(6)所示化合物的方法,其特征在于,所述方法还包括由式(4)化合物制备式(5)化合物,
本发明的另一方面涉及一种制备通式(6)所示化合物的方法,其特征在于,所述方法还包括由式(3)化合物制备式(4)化合物,
本发明的另一方面涉及一种制备通式(6)所示化合物的方法,其特征在于,所述方法还包括由式(2)化合物制备式(3)化合物,
本发明的另一方面涉及一种制备通式(6)所示化合物的方法,其特征在于,所述方法还包括由式(1)化合物制备式(2)化合物,
本发明进一步涉及一种化合物如式(5)所示,
其中,Ra、R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(5)所示化合物的方法,其特征在于,所述方法包括由式(4)化合物制备式(5)化合物,
本发明的另一方面涉及一种制备通式(5)所示化合物的方法,其特征在于,所述方法还包括由式(3)化合物制备式(4)化合物,
本发明的另一方面涉及一种制备通式(5)所示化合物的方法,其特征在于,所述方法还包括由式(2)化合物制备式(3)化合物,
本发明的另一方面涉及一种制备通式(5)所示化合物的方法,其特征在于,所述方法还包括由式(1)化合物制备式(2)化合物,
本发明进一步涉及一种化合物如式(4)所示,
其中,Ra、R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(4)所示化合物的方法,其特征在于,所述方法包括由式(3)化合物制备式(4)化合物,
本发明的另一方面涉及一种制备通式(4)所示化合物的方法,其特征在于,所述方法还包括由式(2)化合物制备式(3)化合物,
本发明的另一方面涉及一种制备通式(4)所示化合物的方法,其特征在于,所述方法还包括由式(1)化合物制备式(2)化合物,
本发明进一步涉及一种化合物如式(3)所示,
其中,R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(3)所示化合物的方法,其特征在于,所述方法包括由式(2)化合物制备式(3)化合物,
本发明的另一方面涉及一种制备通式(3)所示化合物的方法,其特征在于,所述方法还包括由式(1)化合物制备式(2)化合物,
优选的,本发明提供一种式(3-1)所示化合物,
本发明还提供式(3-1)所示化合物的制备方法,其方法与式(3)所示化合物的制备方法相同。
本发明的另一方面涉及一种制备通式(6)所示化合物的方法,其特征在于,所述化合物具有下述式(6-1)所示的结构,
其中,
Ra、R1、R2、如式(6)中的定义;
Ra优选为F原子;
R1优选为任选取代的苯基或吡啶基,所述取代基选自甲基;
R2优选为氢原子。
本发明还提供式(6-1)所示化合物的制备方法,其方法与式(6)所示化合物的制备方法相同。
优选的,本发明提供一种式(6-2)所示化合物,
本发明还提供式(6-2)所示化合物的制备方法,其方法与式(6)或(6-1)所示化合物的制备方法相同。
本发明的另一方面涉及一种制备通式(5)所示化合物的方法,其特征在于,所述化合物具有下述式(5-1)所示的结构,
其中,
Ra、R1、R2、如式(5)中的定义;
Ra优选为F原子;
R1优选为任选取代的苯基或吡啶基,所述取代基选自甲基;
R2优选为氢原子。
本发明还提供式(5-1)所示化合物的制备方法,其方法与式(5)所示化合物的制备方法相同。
优选的,本发明提供一种式(5-2)所示化合物,
本发明还提供式(5-2)所示化合物的制备方法,其方法与式(5)或(5-1)所示化合物的制备方法相同。
本发明的另一方面涉及一种制备通式(4)所示化合物的方法,其特征在于,所述化合物具有下述式(4-1)所示的结构,
其中,
Ra、R1、R2、如式(4)中的定义;
Ra优选为F原子;
R1优选为任选取代的苯基或吡啶基,所述取代基选自甲基;
R2优选为氢原子。
本发明还提供式(4-1)所示化合物的制备方法,其方法与式(4)所示化合物的制备方法相同。
优选的,本发明提供一种式(4-2)所示化合物,
本发明还提供式(4-2)所示化合物的制备方法,其方法与式(4)或(4-1)所示化合物的制备方法相同。
本发明进一步涉及一种化合物如式(2)所示,
其中,
R2选自氢原子、卤素或任选取代的C1-6烷基,所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基,3-14元环烷基优选为3-8元环烷基,3-14元杂环基优选为3-8元杂环基,6-14元芳基优选为6-8元芳基,5-15元杂芳基优选为5-8元杂芳基;R2优选为氢原子;
X选自卤素,优选为氯原子。
优选的,本发明提供一种式(2-1)所示化合物,
本发明进一步涉及一种化合物如式(1)所示,
其中,
R2选自氢原子、卤素或任选取代的C1-6烷基,所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基,3-14元环烷基优选为3-8元环烷基,3-14元杂环基优选为3-8元杂环基,6-14元芳基优选为6-8元芳基,5-15元杂芳基优选为5-8元杂芳基;R2优选为氢原子。
优选的,本发明提供一种式(1-1)所示化合物,
本发明的另一方面涉及一种制备通式(IIA)所示化合物的方法,其特征在于,所述方法为
第一步,中间体(1-1)的制备
将丙二酸二甲酯与丙二腈加入到醚类有机溶剂中中,在碱的作用下与甲胺水溶液反应,滴加氢氧化钠溶液,过滤、干燥后得到中间体(1-1),所述醚类有机溶剂包括但不限于甲基叔丁基醚、乙二醇二甲醚、乙二醇单甲醚或四氢呋喃,优选四氢呋喃,所述碱选自1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)或液氨。
第二步,中间体(2-1)的制备
将中间体(1-1)与卤化试剂进行卤代反应后,加水,固体析出,过滤,干燥后得到中间体(2-1),所述卤化试剂选自三氯氧磷、N-氯代丁二酰亚胺、三氯化磷或五氯化磷,优选三氯氧磷。
第三步,中间体(3-1)的制备
中间体(2-1)与3-羟基-6-甲基吡啶加入到极性非质子性有机溶剂中,在惰性气体保护下,在碱的作用下进行取代反应后,加水,固体析出,过滤、洗涤、干燥后得到中间体(3-1),所述惰性气体选自氮气或氩气,所述极性非质子性有机溶剂包括但不限于二甲基亚砜、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺,优选N,N-二甲基乙酰胺;所述碱选自有机碱或无机碱,优选无机碱,所述的无机碱包括但不限于碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、叔丁醇钾、叔丁醇钠、氢氧化钠或氢氧化钾,优选碳酸铯。
第四步,中间体(4-2)的制备
中间体(3-1)与1,2-二氟-4-硝基苯加入到极性非质子性有机溶剂中,在惰性气体保护下,在碱的作用下进行取代反应后,加水,用有机溶剂萃取,有机相减压浓缩后得到中间体(4-2),所述惰性气体选自氮气或氩气,所述极性非质子性有机溶剂包括但不限于二甲基亚砜、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺,所述萃取有机溶剂包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、二氯甲烷、三氯甲烷或甲基叔丁基醚,所述碱选自有机碱或无机碱,优选无机碱,所述的无机碱包括但不限于碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、叔丁醇钾、叔丁醇钠、氢氧化钠或氢氧化钾,优选碳酸铯。
第五步,中间体(5-2)的制备
中间体(4-2)在强氧化剂作用下进行氧化反应,去除过量的氧化剂,析晶、过滤、干燥后得到中间体(5-2),所述强氧化剂包括但不限于硫酸、过氧化氢、高锰酸钾、二氧化锰,优选硫酸。
第六步,中间体(6-2)的制备
中间体(5-2)发生还原反应后,过滤、滤液浓缩后得到中间体(6-2),所述还原反应可以选自铁粉还原(铁粉与盐酸、乙酸或氯化铵配合)、锌粉还原(锌粉与盐酸、乙酸或氯化铵配合)、金属催化剂催化氢化(兰尼镍,钯炭等为催化剂,通入氢气作为还原剂)、无机盐类还原剂还原法(硫化钠、连二亚硫酸钠或硼氢化钠等作为还原剂)、水合肼还原法(水合肼作为还原剂)等,优选钯碳/乙酸条件下进行还原。
第七步,中间体IIA的制备
式(6-2)化合物在低温条件、酸水溶液中和亚硝酸钠作用下生成重氮化合物,再与碘化钾发生碘代反应,反应结束后,过滤,滤饼加入弱还原性水溶液中打浆,过滤、干燥后得到目标产物IIA,所述的酸水溶液选自盐酸或硫酸,优选盐酸,所述盐酸包含稀盐酸和浓盐酸,优选浓盐酸,所述低温选自0-5℃,所述弱还原性水溶液选自亚硫酸钠水溶液、亚硫酸氢钠水溶液、硫代硫酸钠水溶液等。
本发明的另一方面涉及一种制备如通式(II)所示化合物或上述方案所述IIA所示化合物的药学上可接受的盐方法,包括上述方案所述的制备式(II)所示化合物的步骤,还包括与酸反应制备得到式(II)所示化合物或IIA所式化合物的药学上可接受的盐的步骤,所述酸选自有机酸或无机酸,优选有机酸;所述有机酸选自对甲苯磺酸、苯磺酸或甲磺酸,优选对甲苯磺酸;所述无机酸选自盐酸、硫酸或磷酸。
发明详述
为了更容易理解本发明,以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义,否则本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
本发明所述的“打浆”是指利用物质在溶剂中溶解性差,但杂质在溶剂中溶解性好的特性进行纯化的方法,打浆提纯可以去色、改变晶型或去除少量杂质。
本发明所述“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基,包括例如“C1-4烷基”、“C1-3烷基”等,具体实例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述的“3-14元环烷基”指饱和或部分不饱和单环或多环环状烃取代基,其包括3至14个碳原子,优选包括3至12个碳原子,更优选环烷基环包含3至8个碳原子,最优选环烷基环包含5至6个碳原子,最佳为环丙基。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
本发明所述的“3-14元杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包括3至14个环原子,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包括3至12个环原子,其中1-4个是杂原子,更优选杂环基环包含3至8个环原子,更优选杂环基环包含5至6个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
本发明所述的“6-14元芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至8元的芳基,更优选苯基和萘基,最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,非限制性实施例包含:
本发明所述的“5-15元杂芳基”指具有共轭的π电子体系的5至15元全碳单环或稠合多环基团,进一步包含1至4个杂原子的,其中杂原子选自一个或多个氧、硫或氮。优选为5至8元的杂芳基,更优选为5元至6元的杂芳基,甚至更优选呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含:
本发明所述的“C1-6烷氧基”指-O-(烷基)和-O-(未取代的环烷基),其中C1-6烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
本发明所述的“卤代C1-6烷基”指烷基上的氢原子被一个或多个卤素取代,其中烷基的定义如上所述。
本发明所述的“C1-6烷基氨基羰基、C1-6烷基羰基氨基”分别指C1-6烷基-NH-CO-、C1-6烷基-CO-NH-,其中C1-6烷基的定义如上所述。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物,具体实例包括但不限于:甲基叔丁基醚、乙二醇二甲醚、乙二醇单甲醚或四氢呋喃。
本发明所述的“极性非质子性有机溶剂”是指是由不对称结构的极性分子构成的不含有活泼氢原子的液体化合物;具体实例包括但不限于:二甲基亚砜、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
本发明所述的“卤化试剂”指在单质或化合物分子中引入卤素原子以生产卤化物的反应过程中提供卤素的化合物简称卤化试剂,具体实例包括但不限于:氯气、液溴、三溴化磷、三氯氧磷、三氯化磷、五氯化磷、次氯酸叔丁酯、N-溴(氯)代丁二酰亚胺等。本发明所述的“金属催化剂”指一种在化学反应里能改变反应物化学反应速率(提高或降低)而不改变化学平衡,且本身的质量和化学性质在化学反应前后都没有发生改变的金属材料,一般为过渡金属,具体实例包括但不限于:兰尼镍(Raney-Ni)、钯炭(Pd/C)、铂(Pt)、钌(Ru)等。
本发明所述的“酸”是指有机酸或无机酸,“有机酸”指按照广义的酸碱理论,能接受电子对的化合物。有机酸包括羧酸、卤代酸、羟基酸、酮酸、氨基酸、磺酸、亚磺酸、硫羧酸、酚酸等,优选磺酸,磺酸的具体实例包括但不限于:甲磺酸、十二烷基苯磺酸、苯磺酸、对甲苯磺酸、三氟甲磺酸等;“无机酸”指能解离出氢离子的无机化合物,按照组成成分,无机酸可分成含氧酸、无氧酸、络合酸、混酸、超酸等,优选含氧酸或无氧酸,含氧酸的具体实例包括但不限于:碳酸、硝酸、亚硝酸、次氯酸、硫酸或磷酸等;无氧酸的具体实例包括但不限于:氢氟酸、盐酸、溴酸或氢硫酸等,优选硫酸。
本发明所述的“碱”是指有机碱或无机碱,“有机碱”指按照广义的酸碱理论,碱就是能给出电子对的化合物,有机碱分为胺类、酰胺类、醇的碱金属盐类、烷基金属锂化合物、氨基锂化合物、氨基钠化合物、含氮的杂环化合物、提供氢氧根的有机碱、氨基酸等,具体实例包括但不限于:二甲胺、三乙胺、乙二胺、秋水仙碱、甲醇钠、乙醇钾、叔丁醇锂、叔丁醇钠、叔丁醇钾、正丁基锂、二异丙基氨基锂(LDA)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、氨基钠、吡咯烷、吡啶、四甲基氢氧化铵、赖氨酸(Lys)等。“无机碱”指能解离出氢氧根离子的无机化合物,按照组成成分,无机碱可分成金属氢氧化物、氨水或一水合氨、能够解离出氢氧根离子的盐等,具体实例包括但不限于:氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、碳酸钠(纯碱)、碳酸钾、碳酸氢钠(小苏打)、碳酸氢钾、碳酸铯等。
本发明所述的“强氧化剂”是指在氧化还原反应中,有较强的获得电子能力的物质,具体实例包括但不限于:硫酸、过氧化氢、高锰酸钾、二氧化锰等。
本发明所述的“药学上可接受的盐或可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性,具体为本发明化合物与无机酸或有机酸形成的化合物,具体实例包括但不限于:氢卤酸盐、碳酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、草酸盐、酒石酸盐、马来酸盐、富马酸盐、磺酸盐、氨基酸盐等。
发明的有益效果
与现有技术相比,本发明制备式(II)所示化合物的技术方案具有以下优点:
(1)反应步骤减少,现有技术公开的反应步骤为11步,本发明的反应步骤为7步。
(2)与现有技术比较,本发明的起始原料和中间体不相同,提供了一种完全不同思路的合成方法,并且起始原料和反应物均简单、易购买。
(3)现有技术方法中的每一步反应所得的中间体基本均未进行纯化直接进行下一步反应,本发明方法中的每一个中间体均在反应后处理过程中进行纯化后再投入下一步反应,利于提高产物纯度,避免复杂杂质的出现。
(4)避免高温反应,降低反应危险;反应的后处理简单,易于工业扩大生产。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQadvantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Agilent Plus C18 150×4.6mm色谱柱)。
实施例1、2-(2-氟-4-碘苯氨基)-1-甲基-4-(6-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(化合物31或IIA)的制备
第一步
2-氨基-4-羟基-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(1-1)
将丙二酸二甲酯(39.6g,0.3mol)、丙二腈(19.8g,0.3mol)和四氢呋喃(200ml)加入反应瓶中,氩气保护条件下,-25℃滴加1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU,91.34g,0.6mol),1小时滴加完毕,室温搅拌反应18h,滴加30%甲胺水溶液(200ml),室温搅拌24h。滴加氢氧化钠溶液(10N,45ml)后室温搅拌,反应5h,冰浴下,加丙酮搅拌30min过滤,收集滤饼,减压干燥,得到标题产物(40g,浅黄色固体),产率80.8%。
MS m/z(ESI):166.2[M+1]
第二步
2-氨基-4-氯-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(2-1)
将2-氨基-4-羟基-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(25g,151.51mmol)和乙腈(250ml)加入反应瓶中,冰浴下滴加三氯氧磷(92.9g,605.88mmol),40min滴加完毕,搅拌20分钟,升温至70℃,反应12h,将反应液滴加到冰水(500ml)中,析出大量固体,过滤,滤饼用水(100ml×2)洗涤,母液用饱和KOH调节pH到7,过滤,滤饼合并用丙酮打浆,减压干燥,得到标题产物(15g,浅黄色固体),产率54.0%。
MS m/z(ESI):184.2[M+1]
第三步
2-氨基-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(3-1)
将2-氨基-4-氯-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(4.5g,24.59mmol)和3-羟基-6-甲基吡啶(2.95g,27.0mmol)溶于二甲基乙酰胺(67.5ml)中,加入碳酸铯(15.98g,49.18mmol),氩气保护下,150℃反应18小时,冷却至室温,倒入冰水(300ml)中,析出固体,继续搅拌30min,过滤,滤饼用水(200ml×1)洗涤,减压干燥,得到标题产物(4.5g,类白色固体),产率71.6%。
MS m/z(ESI):257.2[M+1]
第四步
2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(4-2)
将2-氨基-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(12g,43.68mmol)、1,2-二氟-4-硝基苯(7.29g,45.9mmol)和碳酸铯(21.3g,65.5mmol)加入反应瓶中,加入二甲基乙酰胺(120ml),氩气保护下,120℃反应6小时,将反应液倒入冰水(500ml)中,搅拌10分钟,用乙酸乙酯(200ml×3)萃取,合并有机相,用饱和氯化钠溶液(300ml×1)洗涤,用无水硫酸镁干燥,过滤,滤液减压浓缩,得到红色固体,用正己烷(150ml)打浆,得到标题产物(17.2g,红色固体),产率100%。
MS m/z(ESI):396.1[M+1]
第五步
2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(5-2)
将硫酸(90%,170ml)加入反应瓶中,2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(17.2g,43.5mmol)分批加入,缓慢加热,100℃反应40min,将反应液缓慢倒入碎冰(170ml)中,冰浴条件下,滴加氨水调节pH至8,过滤,滤饼用丙酮(80ml)打浆,得到标题产物(11.4g,浅黄色固体),产率60%。
MS m/z(ESI):414.1[M+1]
第六步
2-((4-氨基-2-氟苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(6-2)
反应瓶中依次加入2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(320g,0.77mol)、乙酸(6kg)和10%Pd/C(35g),搅拌均匀,氮气置换3次,氢气置换3次,40-45℃常压加氢反应4-5h,趁热将反应液过滤,滤液减压浓缩后加入乙酸乙酯(4kg)室温打浆2-3h,过滤,滤饼抽干,加入乙酸乙酯(2kg)打浆2-3h,过滤,滤饼用乙酸乙酯洗涤,减压干燥,得产物(207.7g,收率70.0%,HPLC检测纯度不低于96%)。
MS m/z(ESI):384.1[M+1]
第七步
2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(31or IIA)
反应瓶中投入2-((4-氨基-2-氟苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(180g,0.47mol)和盐酸(1.4kg),搅拌均匀,在0-5℃下缓慢滴加535.7g亚硝酸钠溶液中(配置方式:35.7g亚硝酸钠溶解在500g水中),0-5℃下,将上述溶液滴加到1234g碘化钾溶液中(配置方式:234g碘化钾溶于1kg纯化水),室温搅拌反应18-20h,过滤,滤饼用纯化水(200g)洗涤,将滤饼加入(6kg)硫代硫酸钠的水溶液中(配置方式:3kg硫代硫酸钠溶解在3kg纯化水中)室温打浆0.5-1h,过滤,滤饼用水(500g)洗,干燥后中性氧化铝柱层析纯化(二氯甲烷∶乙酸乙酯=4∶1~1∶4),收集正组分,减压浓缩后,加入丙酮(500g)室温打浆1-2h,过滤,减压干燥得产物(60.3g,收率26.0%,HPLC检测纯度不低于96%)。
MS m/z(ESI):494.1[M+1]
1H-NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.38-8.44(m,1H),7.57-7.75(m,4H),7.35-7.49(m,2H),6.65(t,1H),5.09(s,1H),3.15(s,3H),2.51(s,3H).
实施例2、2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐的制备
(1)粗品的制备
反应瓶中投入2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(43g,0.09mol)、对甲苯磺酸(19.0g,0.10mol)和异丙醇(1.0kg),回流反应2-2.5h。停止加热,继续搅拌12-14h,停止反应,过滤,滤饼用异丙醇洗涤,减压干燥,得产物(56.2g,收率97.0%,HPLC检测纯度不低于97%)。
(2)产品的纯化
反应瓶中投入2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐粗品(52.9g,0.08mol),丙酮(715g),纯化水(120g),加热回流,搅拌溶解,趁热过滤,滤液加入丙酮(1.6kg),室温搅拌16-18h,冰浴搅拌2-3h,过滤,滤饼用丙酮洗涤,40-45℃减压干燥4-5h,得目标产物(42.3g,收率80.0%,HPLC检测纯度不低于98%)。
MS m/z(ESI):494.1[M+1]
1H-NMR(400 MHz,DMSO-d6)δ9.72(s,1H),8.82-8.83(d,1H),8.25-8.28(dd,1H),7.85-7.88(d,1H),7.70(br,1H),7.65(br,1H),7.63-7.66(dd,1H),7.48-7.50(d,2H),7.42-7.44(dd,1H),7.11-7.13(d,2H),6.66-6.70(t,1H),5.42(s,1H),3.19(s,3H),2.67(s,3H),2.29(s,3H).
Claims (38)
2.如权利要求1所述的制备方法,其特征在于,R1选自任选取代的苯基或吡啶基,所述取代基选自C1-6烷基、卤素、卤代C1-6烷基、C1-6烷氧基、C1-6烷基氨基羰基、C1-6烷基羰基氨基、3-8元杂环基氧基、3-8元环烷基氨基羰基、3-8元环烷基羰基氨基或C1-6烷基磺酰氨基。
3.如权利要求1所述的制备方法,其特征在于,R2选自氢原子、卤素或任选取代的C1-6烷基,所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-8元环烷基、3-8元杂环基、6-8元芳基或5-8元杂芳基。
35.一种制备如权利要求1所述通式(II)所示化合物或权利要求34所述IIA所示化合物的药学上可接受的盐方法,包括权利要求1-8中任一项所述的制备式(II)所示化合物的步骤或权利要求34中制备式IIA所式化合物的步骤,还包括与酸反应制备得到式(II)所示化合物或IIA所式化合物的药学上可接受的盐的步骤,所述酸选自有机酸或无机酸。
36.如权利要求35所述的方法,其特征在于,所述无机酸选自盐酸、硫酸或磷酸。
37.如权利要求35所述的方法,其特征在于,所述酸选自有机酸,所述有机酸选自对甲苯磺酸、苯磺酸或甲磺酸。
38.如权利要求37所述的方法,其特征在于,所述有机酸选自对甲苯磺酸。
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