TWI755667B - Preparation method of fused tricyclic derivatives and intermediates thereof - Google Patents

Preparation method of fused tricyclic derivatives and intermediates thereof Download PDF

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TWI755667B
TWI755667B TW108148250A TW108148250A TWI755667B TW I755667 B TWI755667 B TW I755667B TW 108148250 A TW108148250 A TW 108148250A TW 108148250 A TW108148250 A TW 108148250A TW I755667 B TWI755667 B TW I755667B
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李瑤
王文晶
張國彪
石宗軍
陳雷
張晨
嚴龐科
鄭偉
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大陸商四川海思科製藥有限公司
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    • C07C229/00Compounds containing amino and carboxyl groups bound to the same carbon skeleton
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Abstract

本發明提供了一種稠合三環衍生物的製備方法及中間體。所述稠合三環衍生物具有式(I)所示的結構。所述製備方法原料易得、步驟簡單,適宜大規模工業化生產。

Figure 108148250-A0101-11-0001-1
。The invention provides a preparation method and an intermediate of a fused tricyclic derivative. The fused tricyclic derivative has the structure represented by formula (I). The preparation method has easy-to-obtain raw materials and simple steps, and is suitable for large-scale industrial production.
Figure 108148250-A0101-11-0001-1
.

Description

稠合三環衍生物的製備方法及其中間體Preparation method of fused tricyclic derivatives and intermediates thereof

本發明涉及醫藥領域,具體來說,本發明涉及一種稠合三環衍生物的製備方法及中間體。 The present invention relates to the field of medicine, in particular to a preparation method and an intermediate of a fused tricyclic derivative.

電壓門控鈣離子通道由α1亞單位和輔助蛋白α2δ、β、γ亞基共同構成。α2δ蛋白可以調節鈣離子通道的密度及鈣離子通道電壓依賴性動力學(Felix et al(1997)J.Neuroscience 17:6884-6891;Klugbauer et al(1999)J.Neuroscience 19:684-691;Hobom et al(2000)Eur.J.Neuroscience 12:1217-1226;and Qin et al(2002)Mol.Pharmacol.62:485-496)。已經證實,對電壓依賴性鈣離子通道亞基α2δ表現出高親合力結合的化合物可有效治療疼痛,例如普瑞巴林和加巴噴丁。在哺乳動物中,α2δ蛋白有4個亞型,每個亞型均由不同的基因編碼。α2δ亞型1和亞型2與普瑞巴林表現出高親和力,而α2δ亞型3和亞型4無顯著的藥物結合力。 Voltage-gated calcium channels are composed of α1 subunit and accessory protein α2δ, β, γ subunits. α2δ proteins can modulate calcium channel density and calcium channel voltage-dependent kinetics (Felix et al (1997) J. Neuroscience 17:6884-6891; Klugbauer et al (1999) J. Neuroscience 19:684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). Compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ have been shown to be effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, there are four isoforms of α2δ proteins, each encoded by a different gene. α2δ isoforms 1 and 2 showed high affinity for pregabalin, while α2δ isoforms 3 and 4 showed no significant drug binding.

然而,對於加巴噴丁,其較大程度改善糖尿病周圍神經病變患者病痛的比例約為60%(Acta Neurol.Scand.101:359-371,2000),對於普瑞巴林,雖然其耐受性優於加巴噴丁,但其安全性更低,且有濫用或者使患者產生依賴的可能(Am J Health Syst Pharm.2007;64(14):1475-1482)。 However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy is about 60% improved (Acta Neurol. Scand. 101: 359-371, 2000), for pregabalin, although it is better tolerated than gabapentin , but its safety is lower, and there is the possibility of abuse or dependence of patients (Am J Health Syst Pharm. 2007; 64 (14): 1475-1482).

開發新的對電壓依賴性鈣離子通道亞基α2δ表現出高親合力結合的化合物仍然有很大的需求。 There remains a great need to develop new compounds that exhibit high-affinity binding to the voltage-dependent calcium channel subunit α2δ.

PCT/CN2017/101364專利申請公開了一種稠合三環γ-氨基酸衍生物及其製備方法和在醫藥上的應用,它們具有良好的生物活性,同時也公開了製 備該衍生物的中間體式(I)化合物及其製備方法,

Figure 108148250-A0305-02-0003-1
式(I)。 The PCT/CN2017/101364 patent application discloses a fused tricyclic γ-amino acid derivative and its preparation method and application in medicine, which have good biological activity, and also discloses the intermediate formula (I) for preparing the derivative. ) compounds and methods for their preparation,
Figure 108148250-A0305-02-0003-1
Formula (I).

本發明的目的在於提供用於製備式(I)稠合三環衍生物的方法。 The object of the present invention is to provide a method for preparing a fused tricyclic derivative of formula (I).

本發明的另一目的在於提供用於製備式(I)稠合三環衍生物的中間體的方法。 Another object of the present invention is to provide a method for preparing intermediates of the fused tricyclic derivatives of formula (I).

本發明再一目的在於提供製備式(I)所述化合物及其立體異構體或其藥學上可接受鹽的中間體。 Another object of the present invention is to provide intermediates for preparing the compounds of formula (I) and their stereoisomers or their pharmaceutically acceptable salts.

本發明涉及一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,通過式(3-10)化合物製備得到;

Figure 108148250-A0305-02-0003-2
The present invention relates to a preparation method of a compound of formula (I) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is prepared from a compound of formula (3-10);
Figure 108148250-A0305-02-0003-2

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在鹼性條件下與酸酐或醯氯反應製備得到式(I)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by reaction with chlorine.

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在鹼性條件下與酸酐或 醯氯反應製備得到式(I)化合物,所述的酸酐選自三氟甲磺酸酐、三氟乙酸酐;醯氯選自三氯氧磷、草醯氯、三光氣或氯化亞碸。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or The compound of formula (I) is prepared by reacting acyl chloride, and the acid anhydride is selected from trifluoromethanesulfonic anhydride and trifluoroacetic anhydride; the acyl chloride is selected from phosphorus oxychloride, oxalyl chloride, triphosgene or thionous chloride.

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在鹼性條件下與酸酐或醯氯反應製備得到式(I)化合物,所述的鹼選自有機鹼,較佳為Collidine、2,4,6-三甲基吡啶、2-氟吡啶、2,6-二第三丁基-4-甲基吡啶、2,6-二第三丁基吡啶、六甲基亞磷醯三胺、三乙胺、N,N-二異丙基乙胺或DBU(1,8-二氮雜雙環[5.4.0]十一碳-7-烯)。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the base is selected from organic bases, preferably Collidine, 2,4,6-trimethylpyridine, 2-fluoropyridine, 2,6-di-tert-butyl- 4-methylpyridine, 2,6-di-tert-butylpyridine, hexamethylphosphine triamine, triethylamine, N,N-diisopropylethylamine or DBU(1,8-diazepine bicyclo[5.4.0]undec-7-ene).

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在鹼性條件下與酸酐或醯氯反應製備得到式(I)化合物,其中進一步在鹼性條件下反應,所述的鹼選自無機鹼,較佳為金屬鹼,進一步較佳為碳酸鉀、碳酸鈉、碳酸銫、磷酸鉀、磷酸鈉、氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸氫鈉或碳酸氫鉀。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. Chlorine reaction is prepared to obtain the compound of formula (I), wherein the reaction is further performed under alkaline conditions, and the base is selected from inorganic bases, preferably metal bases, further preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, Sodium Phosphate, Lithium Hydroxide, Sodium Hydroxide, Potassium Hydroxide, Sodium Bicarbonate or Potassium Bicarbonate.

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在鹼性條件下與酸酐或醯氯反應製備得到式(I)化合物,(3-10)化合物與酸酐或醯氯的摩爾比選自1:1-1:4,較佳為1:1.5-1:2。本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在鹼性條件下與酸酐或醯氯反應製備得到式(I)化合物,反應使用的溶劑選自水、二氯甲烷、丙酮或1,2-二氯乙烷。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the molar ratio of compound (3-10) to acid anhydride or acyl chloride is selected from 1:1-1:4, preferably 1:1.5-1:2. Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the solvent used in the reaction is selected from water, dichloromethane, acetone or 1,2-dichloroethane.

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在鹼性條件下與酸酐或醯氯反應製備得到式(I)化合物,反應溫度選自0℃至回流。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the reaction temperature is selected from 0°C to reflux.

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-10)化合物在有機鹼存在下與酸酐或醯氯反應得到中間體亞胺鹽,然後在鹼性條件下反應製備得到式(I)化合物,所述的酸酐選自三氟甲磺酸酐或三氟乙酸酐;醯氯選自三氯氧磷、草醯氯、三光氣或氯化亞碸;所述有機鹼選自Collidine、2,4,6-三甲基吡啶、2-氟吡啶、2,6-二第三丁基-4-甲基吡啶、2,6-二第三丁基吡啶、六甲基亞磷醯三胺、三乙胺、N,N-二異丙基乙胺或DBU(1,8-二氮雜雙環[5.4.0]十一碳-7-烯); 所述的鹼選自無機鹼,較佳為金屬鹼,進一步較佳為碳酸鉀、碳酸鈉、碳酸銫、磷酸鉀、磷酸鈉、氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸氫鈉或碳酸氫鉀。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or amide in the presence of an organic base Chlorine reacts to obtain the intermediate imide salt, and then reacts under alkaline conditions to prepare the compound of formula (I), and the acid anhydride is selected from trifluoromethanesulfonic anhydride or trifluoroacetic anhydride; Oxalyl chloride, triphosgene or sulfite chloride; the organic base is selected from Collidine, 2,4,6-collidine, 2-fluoropyridine, 2,6-di-tert-butyl-4-methyl Pyridine, 2,6-di-tert-butylpyridine, hexamethylphosphoric triamine, triethylamine, N,N-diisopropylethylamine or DBU(1,8-diazabicyclo[5.4. 0]undec-7-ene); The base is selected from inorganic bases, preferably metal bases, further preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate or Potassium bicarbonate.

本發明涉及一種式((3-10)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中包括通過式(3-9)化合物製備得到式(3-10)化合物,

Figure 108148250-A0305-02-0005-3
The present invention relates to a preparation method of the compound of formula ((3-10) and its stereoisomers or pharmaceutically acceptable salts thereof, which comprises preparing the compound of formula (3-9) to obtain the compound of formula (3-10) ,
Figure 108148250-A0305-02-0005-3

本發明的一些具體實施例,一種式((3-10)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-9)化合物、吡咯烷、縮合劑在鹼性條件下反應製備得到式(3-10)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) can be obtained by reacting under basic conditions.

本發明的一些具體實施例,一種式((3-10)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-9)化合物、吡咯烷、縮合劑在鹼性條件下反應製備得到式(3-10)化合物;所述的縮合劑選自1-(3-二甲胺基丙基)-3-乙基碳二亞胺(EDCI)、羰基二咪唑(CDI)、二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)、甲烷磺醯氯(MsCl)、對甲苯磺醯氯(TsCl)、對硝基苯磺醯氯(NsCl)、O-(7-氮雜苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽(HATU)、O-(苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽(HBTU)、O-(5-氯苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽(HCTU)、O-(苯並三氮唑-1-基)-二(二甲胺基)碳鎓四氟硼酸鹽(TBTU)、O-(N-丁二醯亞胺基)-二(二甲胺基)碳鎓四氟硼酸鹽(TSTU)、O-(N-endo-5-降莰烯-2,3-二碳二醯亞胺)-二(二甲胺基)碳鎓四氟硼酸鹽(TNTU)、苯基磷醯氯(DPP-Cl)、氰代磷酸二乙酯(DECP)、疊氮化磷酸二苯酯(DPPA)、硫代二甲基磷醯基疊氮(MPTA)或二(2-氧-3-唑烷基)磷醯氯(BOP-Cl)。 Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) is prepared by reacting under basic conditions; the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), carbonyl diimide Imidazole (CDI), Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), Methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), p-nitrobenzenesulfonic acid Acyl chloride (NsCl), O-(7-azabenzotriazole-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazole- 1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate Phosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-butanediimidinyl)- Bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbon Onium tetrafluoroborate (TNTU), phenylphosphonium chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphonium azide Nitrogen (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphonium chloride (BOP-Cl).

本發明的一些具體實施例,一種式((3-10)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-9)化合物、吡咯烷、縮合劑在鹼性條件下反應製備得到式(3-10)化合物,反應使用的鹼選自有機鹼或無機鹼,較佳為三乙胺、N,N-二異丙基乙胺、4-N,N-二甲基吡啶(DMAP)、1-羥基苯並三氮唑(HOBt)、碳酸鈉或碳酸鉀。 Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) is prepared by reacting under basic conditions, and the base used in the reaction is selected from organic bases or inorganic bases, preferably triethylamine, N,N-diisopropylethylamine, 4- N , N -lutidine (DMAP), 1-hydroxybenzotriazole (HOBt), sodium carbonate or potassium carbonate.

本發明的一些具體實施例,一種式((3-10)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-9)化合物、吡咯烷、縮合劑在鹼性條件下反應製備得到式(3-10)化合物,反應使用的溶劑選自二氯甲烷、乙 腈、乙酸乙酯、四氫呋喃、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二甲基亞碸和N-甲基吡咯烷酮中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) is prepared by reacting under basic conditions, and the solvent used in the reaction is selected from dichloromethane, ethyl acetate Any one or any of several in nitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and N-methylpyrrolidone proportion of the mixture.

本發明的一些具體實施例,一種式(3-10)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-9)化合物、吡咯烷、縮合劑在鹼性條件下反應製備得到式(3-10)化合物,式(3-9)化合物與吡咯烷的摩爾比為1:1-1:3,較佳為1:1-1:2。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-10) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine and condensing agent are in The compound of formula (3-10) is prepared by the reaction under basic conditions, and the molar ratio of the compound of formula (3-9) to pyrrolidine is 1:1-1:3, preferably 1:1-1:2.

本發明的一些具體實施例,一種式(3-10)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-9)化合物、吡咯烷、縮合劑在鹼性條件下反應製備得到式(3-10)化合物,反應溫度選自0℃至回流,較佳為0-40℃。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-10) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine and condensing agent are in The compound of formula (3-10) is prepared by reacting under basic conditions, and the reaction temperature is selected from 0°C to reflux, preferably 0-40°C.

本發明涉及一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中包括通過式(3-8)化合物製備得到式(3-9)化合物

Figure 108148250-A0305-02-0007-4
The present invention relates to a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, which comprises preparing the compound of formula (3-8) to obtain the compound of formula (3-9)
Figure 108148250-A0305-02-0007-4

本發明的一些具體實施例,一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared.

本發明的一些具體實施例,一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物;所述氧化劑選自NaClO2、重鉻酸吡啶嗡鹽(PDC)、高錳酸鉀、高碘酸鈉/三氯化釕、雙氧水/甲酸或二乙酸碘苯/2,2,6,6-四甲基呱啶氧化物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared; the oxidant is selected from NaClO 2 , pyridinium dichromate (PDC), potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid or iodine diacetate Benzene/2,2,6,6-tetramethylpyridine oxide.

本發明的一些具體實施例,一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物;所述氧化劑為2-甲基-2-丁烯/NaClO2/NaH2PO4Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared; the oxidant is 2-methyl-2-butene/NaClO 2 /NaH 2 PO 4 .

本發明的一些具體實施例,一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物,反應使用的溶劑選自水、第三丁醇、二氯甲烷、丙酮、二氧六環和甲苯中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the solvent used in the reaction is selected from any one of water, tert-butanol, dichloromethane, acetone, dioxane and toluene, or a mixture of any of them in any proportion.

本發明的一些具體實施例,一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物,式(3-8)化合物與氧化劑的摩爾比為1:1-1:4,較佳為1:3。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the molar ratio of the compound of formula (3-8) to the oxidant is 1:1-1:4, preferably 1:3.

本發明的一些具體實施例,一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物,反應溫度選自0-40℃。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the reaction temperature is selected from 0-40°C.

本發明的一些具體實施例,一種式(3-9)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物,所述氧化劑選自NaClO2、重鉻酸吡啶嗡鹽(PDC)、高錳酸鉀、高碘酸鈉/三氯化釕、雙氧水/甲酸、二乙酸碘苯/2,2,6,6-四甲基呱啶氧化物,較佳為2-甲基-2-丁烯/NaClO2/NaH2PO4;反應使用的溶劑選自水、第三丁醇、二氯甲烷、丙酮、二氧六環和甲苯中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the oxidant is selected from NaClO 2 , pyridinium dichromate (PDC), potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid, iodine diacetate Benzene/2,2,6,6-tetramethylpyridine oxide, preferably 2-methyl-2-butene/NaClO 2 /NaH 2 PO 4 ; the solvent used in the reaction is selected from water, tert-butylene Any one of alcohol, dichloromethane, acetone, dioxane and toluene or a mixture of any of them in any ratio.

本發明涉及一種式(3-8)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,包括通過式(3-7)化合物製備得到式(3-8)化合物,

Figure 108148250-A0305-02-0009-5
The present invention relates to a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-8) by preparing the compound of formula (3-7),
Figure 108148250-A0305-02-0009-5

本發明的一些具體實施例,一種式(3-8)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-7)化合物與氧化劑反應製備得到式(3-8)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compounds.

本發明的一些具體實施例,一種式(3-8)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-7)化合物與氧化劑反應製備得到式(3-8)化合物,所述氧化劑選自鄰碘醯苯甲酸(IBX)、氯鉻酸吡啶鎓鹽(PCC)、三氧化硫吡啶、戴斯-馬丁氧化劑、瓊斯試劑、二甲基亞碸/草醯氯或TPAP([n-Pr4N][RuO4])/N-甲基嗎啉。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the oxidant is selected from o-iodobenzoic acid (IBX), pyridinium chlorochromate (PCC), sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, dimethylsulfite/ Oxalyl chloride or TPAP([n- Pr4N ][ RuO4 ])/N-methylmorpholine.

本發明的一些具體實施例,一種式(3-8)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-7)化合物與氧化劑反應製備得到式(3-8)化合物,反應使用的溶劑選自乙酸乙酯、二氯甲烷、丙酮和二甲基亞碸中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the solvent used in the reaction is selected from ethyl acetate, dichloromethane, acetone and dimethylsulfite, or any mixture in any proportion.

本發明的一些具體實施例,一種式(3-8)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-7)化合物與氧化劑反應製備得到式(3-8)化合物,反應溫度選自0℃至回流。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the reaction temperature is selected from 0°C to reflux.

本發明的一些具體實施例,一種式(3-8)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-7)化合物與氧化劑反應製備得到式(3-8)化合物,式(3-7)化合物與氧化劑的摩爾比選自1:1-1:3。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) The compound, the molar ratio of the compound of formula (3-7) to the oxidizing agent is selected from 1:1-1:3.

本發明的一些具體實施例,一種式(3-8)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-7)化合物與氧化劑反應製備得到式(3-8)化合物,所述氧化劑選自鄰碘醯苯甲酸(IBX)、氯鉻酸吡啶鎓鹽(PCC)、三氧化硫吡啶、戴斯-馬丁氧化劑、瓊斯試劑、二甲基亞碸/草醯氯或TPAP([n-Pr4N][RuO4])/N-甲基嗎啉;反應使用的溶劑選自乙酸乙酯、二氯甲烷、丙酮和二甲基亞碸中的任一種或任幾種任意比例的混合物;式(3-7)化合物與氧化劑的摩爾比選自1:1-1:3;反應溫度選自0℃至回流。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the oxidant is selected from o-iodobenzoic acid (IBX), pyridinium chlorochromate (PCC), sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, dimethylsulfite/ Oxalyl chloride or TPAP([n-Pr 4 N][RuO 4 ])/N-methylmorpholine; the solvent used in the reaction is selected from any of ethyl acetate, dichloromethane, acetone and dimethylsulfoxide. One or any mixture in any ratio; the molar ratio of the compound of formula (3-7) to the oxidant is selected from 1:1-1:3; the reaction temperature is selected from 0°C to reflux.

本發明涉及一種式(3-7)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中包括通過式(3-6)化合物製備得到式(3-7)化合物

Figure 108148250-A0305-02-0010-6
;P選自羥基保護基,較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The present invention relates to a preparation method of the compound of formula (3-7) and its stereoisomers or pharmaceutically acceptable salts thereof, which comprises preparing the compound of formula (3-6) to obtain the compound of formula (3-7)
Figure 108148250-A0305-02-0010-6
; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

本發明的一些具體實施例,一種式(3-7)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,包括通過式(3-6)化合物製備得到式(3-7)化合物其中,反應使用的催化劑選自2,3-二氯-5,6-二氰對苯醌(DDQ)、硝酸鈰銨、三氟甲烷磺酸鈰、Pd/C/H2或四氯化鋯。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-7) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-6) to obtain formula (3- 7) Compound wherein, the catalyst used in the reaction is selected from 2,3-dichloro-5,6-dicyano-p - benzoquinone (DDQ), cerium ammonium nitrate, cerium trifluoromethanesulfonate, Pd/C/H or tetrakis Zirconium chloride.

本發明的一些具體實施例,一種式(3-7)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,包括通過式(3-6)化合物製備得到式(3-7)化合物,反應使用的緩衝溶劑選自pH=7的緩衝溶液,較佳為pH=7的磷酸鉀緩衝溶液、pH=7的磷酸鈉緩衝溶液。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-7) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-6) to obtain formula (3- 7) Compound, the buffer solvent used in the reaction is selected from pH=7 buffer solution, preferably pH=7 potassium phosphate buffer solution, pH=7 sodium phosphate buffer solution.

本發明的一些具體實施例,一種式(3-7)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,包括通過式(3-6)化合物製備得到式(3-7)化 合物,反應使用的溶劑選自二氯甲烷、乙腈、氯苯、甲苯、乙二醇二乙醚和硝基甲烷中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-7) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-6) to obtain formula (3- 7)ization The solvent used in the reaction is selected from any one or a mixture of any of several in any ratio among dichloromethane, acetonitrile, chlorobenzene, toluene, ethylene glycol diethyl ether and nitromethane.

本發明涉及一種式(3-6)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中包括通過式(3-4)化合物製備得到式(3-6)化合物

Figure 108148250-A0305-02-0011-7
;P選自羥基保護基,較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The present invention relates to a preparation method of the compound of formula (3-6) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-4) to obtain the compound of formula (3-6)
Figure 108148250-A0305-02-0011-7
; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

本發明的一些具體實施例,一種式(3-6)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中,

Figure 108148250-A0305-02-0011-8
;式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,
Figure 108148250-A0305-02-0011-8
The compound of formula (3-4) is reacted with the compound of formula (3-5) in the presence of a catalyst to prepare the compound of formula (3-6).

本發明的一些具體實施例,一種式(3-6)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物,所述催化劑選自金屬試劑,較佳為四氯合銅酸二鋰、碘化亞銅、三氯化鈰、氯化鋰或二氯化鋅。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, the catalyst is selected from metal reagents, preferably dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or dichloride Zinc.

本發明的一些具體實施例,一種式(3-6)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物,反應使用的溶劑選自四氫呋喃,甲苯、二氧六環、乙醚、氯苯和二甲基亞碸中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, and the solvent used in the reaction is selected from tetrahydrofuran, any one of toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite in any proportion or in any proportion. mixture.

本發明的一些具體實施例,一種式(3-6)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,式(3-4)化合物與式(3-5)化合物在催化劑存 在下反應製備得到式(3-6)化合物,式(3-4)化合物與式(3-5)化合物的摩爾比為1:1-1:4。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) in the catalyst The compound of formula (3-6) is prepared in the following reaction, and the molar ratio of the compound of formula (3-4) to the compound of formula (3-5) is 1:1-1:4.

本發明的一些具體實施例,一種式(3-6)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物,反應溫度為-78℃-40℃。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, and the reaction temperature is -78°C-40°C.

本發明的一些具體實施例,一種式(3-6)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物,所述催化劑選自金屬試劑,較佳為四氯合銅酸二鋰、碘化亞銅、三氯化鈰、氯化鋰或二氯化鋅;反應使用的溶劑選自四氫呋喃,甲苯、二氧六環、乙醚、氯苯和二甲基亞碸中的任一種或任幾種任意比例的混合物;式(3-4)化合物與式(3-5)化合物的摩爾比為1:1-1:4;反應溫度為-78℃-40℃。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, the catalyst is selected from metal reagents, preferably dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or dichloride Zinc oxide; the solvent used in the reaction is selected from tetrahydrofuran, toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite or any mixture in any proportion; the compound of formula (3-4) and the formula (3-5) The molar ratio of the compound is 1:1-1:4; the reaction temperature is -78°C-40°C.

本發明的一些具體實施例,一種式(3-4)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中包括通過式(3-3)化合物製備得到式(3-4)化合物

Figure 108148250-A0305-02-0012-9
;P選自羥基保護基,較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-3) to obtain formula (3) -4) Compounds
Figure 108148250-A0305-02-0012-9
; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

本發明的一些具體實施例,一種式(3-4)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法其中式(3-3)化合物與金屬鎂在催化劑存在下反應製備得到式(3-4)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-3) is reacted with metal magnesium in the presence of a catalyst The compound of formula (3-4) is prepared.

本發明的一些具體實施例,一種式(3-4)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法其中式(3-3)化合物與金屬鎂在催化劑存在下 反應製備得到式(3-4)化合物,所述催化劑選自碘、1,2-二氯乙烷或異丙基溴化鎂。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-3) and metal magnesium are in the presence of a catalyst The compound of formula (3-4) is prepared by the reaction, and the catalyst is selected from iodine, 1,2-dichloroethane or isopropylmagnesium bromide.

本發明的一些具體實施例,一種式(3-4)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-3)化合物與金屬鎂在催化劑存在下反應製備得到式(3-4)化合物,反應使用的溶劑選自醚類溶劑,較佳為四氫呋喃和乙醚中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-3) and metal magnesium are in the presence of a catalyst The compound of formula (3-4) is prepared by the reaction, and the solvent used in the reaction is selected from ether solvents, preferably any one of tetrahydrofuran and diethyl ether or a mixture of any of them in any proportion.

本發明涉及一種式(3-3)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中包括通過式(3-2)化合物製備得到式(3-3)化合物

Figure 108148250-A0305-02-0013-10
;P選自羥基保護基,較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The present invention relates to a preparation method of the compound of formula (3-3) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-2) to obtain the compound of formula (3-3)
Figure 108148250-A0305-02-0013-10
; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

本發明的一些具體實施例,一種式(3-3)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-2)化合物與溴化試劑在催化劑存在下反應製備得到式(3-3)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) can be obtained by the following reaction.

本發明的一些具體實施例,一種式(3-3)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-2)化合物與溴化試劑在催化劑存在下反應製備得到式(3-3)化合物,反應使用的溶劑選自乙腈、二氯甲烷、水、四氫呋喃、甲苯、乙醚和乙酸乙酯中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) is prepared by the following reaction, and the solvent used in the reaction is selected from any one of acetonitrile, dichloromethane, water, tetrahydrofuran, toluene, ether and ethyl acetate or a mixture of any of them in any proportion.

本發明的一些具體實施例,一種式(3-3)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-2)化合物與溴化試劑在催化劑存在下反應製備得到式(3-3)化合物,所述的催化劑選自膦類化合物,較佳為三苯基膦或三丁基膦等。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) is prepared by the following reaction, and the catalyst is selected from phosphine compounds, preferably triphenylphosphine or tributylphosphine and the like.

本發明的一些具體實施例,一種式(3-3)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-2)化合物與溴化試劑在催化劑存在下反應製備得到式(3-3)化合物,所述的溴化試劑選自四溴化碳、氫溴酸、溴化鈉/硫酸、溴化氰、液溴、三溴化磷、1-丁基-3-甲基咪唑溴鹽或二溴海因。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) is prepared by the lower reaction, and the bromination reagent is selected from carbon tetrabromide, hydrobromic acid, sodium bromide/sulfuric acid, cyanogen bromide, liquid bromine, phosphorus tribromide, 1-butane 3-methylimidazolium bromide or dibromohydantoin.

本發明涉及一種式(3-2)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中包括通過式(3-1)化合物製備得到式(3-2)化合物

Figure 108148250-A0305-02-0014-11
The present invention relates to a preparation method of the compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-1) to obtain the compound of formula (3-2)
Figure 108148250-A0305-02-0014-11

本發明涉及一種式(3-2)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-1)化合物與羥基保護劑反應製備得到式(3-2)化合物。 The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound.

本發明涉及一種式(3-2)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-1)化合物與羥基保護劑反應製備得到式(3-2)化合物。反應使用的鹼選自氫化鈉、氫化鉀、碳酸鉀、碳酸鈉、碳酸銫、三乙胺、N,N-二異丙基乙胺或4-N,N-二甲基吡啶(DMAP)。 The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound. The base used in the reaction is selected from sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine or 4- N , N -lutidine (DMAP).

本發明涉及一種式(3-2)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-1)化合物與羥基保護劑反應製備得到式(3-2)化合物,反應使用的溶劑選自四氫呋喃、丙酮、乙醚、N-甲基吡咯烷酮、N,N-二甲基甲醯胺和甲苯中的任一種或任幾種任意比例的混合物。 The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound, and the solvent used in the reaction is selected from any one or a mixture of any of several in any ratio among tetrahydrofuran, acetone, ether, N-methylpyrrolidone, N,N-dimethylformamide and toluene.

本發明涉及一種式(3-2)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中式(3-1)化合物與羥基保護劑反應製備得到式(3-2)化合 物,反應使用的催化劑選自四丁基碘化銨、碘化鈉、碘化鉀、溴化鈉、溴化鉀或四丁基溴化銨。 The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound The catalyst used in the reaction is selected from tetrabutylammonium iodide, sodium iodide, potassium iodide, sodium bromide, potassium bromide or tetrabutylammonium bromide.

本發明涉及一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,包括以下步驟:

Figure 108148250-A0305-02-0015-12
Figure 108148250-A0305-02-0015-45
,P選自羥基保護基,較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基;a:以式(3-1)化合物為原料,與羥基保護劑反應製備得到式(3-2)化合物;b:以式(3-2)化合物為原料,與溴化試劑反應製備得到式(3-3)化合物;c:以式(3-3)化合物為原料,與金屬鎂反應製備得到式(3-4)化合物;d:以式(3-4)化合物為原料,與式(3-5)化合物製備得到式(3-6)化合物; e:以式(3-6)化合物為原料,與脫保護反應製備得到式(3-7)化合物;f:以式(3-7)化合物為原料,與氧化劑反應製備得到式(3-8)化合物;g:以式(3-8)化合物為原料,與氧化劑反應製備得到式(3-9)化合物;h:以式(3-9)化合物為原料,與吡咯烷在縮合劑存在下,在鹼性條件下反應製備得到式(3-10)化合物;i以式(3-10)化合物為原料,在鹼性條件下與三氟甲磺酸酐反應製備得到式(I)化合物。 The present invention relates to a preparation method of the compound of formula (I) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure 108148250-A0305-02-0015-12
Figure 108148250-A0305-02-0015-45
, P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl; a: take the compound of formula (3-1) as a raw material, react with a hydroxyl protecting agent to prepare a compound of formula (3-2); b: take the compound of formula (3-2) as a raw material, react with a bromination reagent to prepare a compound of formula ( 3-3) compound; c: using the compound of formula (3-3) as a raw material, and reacting with metal magnesium to prepare the compound of formula (3-4); d: using the compound of formula (3-4) as a raw material, and the compound of formula (3) -5) The compound of the formula (3-6) is obtained by preparing the compound; e: the compound of the formula (3-6) is used as the raw material, and the compound of the formula (3-7) is prepared by the deprotection reaction; f: the compound of the formula (3-7) is obtained The compound is used as a raw material, and the compound of formula (3-8) is prepared by reacting with an oxidizing agent; g: the compound of formula (3-8) is prepared by reacting with an oxidizing agent as a raw material; h: the compound of formula (3-9) is prepared by reacting with the oxidizing agent; 9) The compound is a raw material, reacts with pyrrolidine in the presence of a condensing agent under basic conditions to prepare the compound of formula (3-10); i takes the compound of formula (3-10) as a raw material, reacts with three The compound of formula (I) can be obtained by the reaction of fluoromethanesulfonic anhydride.

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中,a:反應使用的羥基保護劑選自對甲氧基苄氯,鹼選自氫化鈉,溶劑選自四氫呋喃、催化劑選自四丁基碘化銨;b:反應使用的溴化試劑選自四溴化碳,溶劑選自乙腈,催化劑選自三苯基膦;c:反應使用的催化劑選自碘,使用的溶劑選自四氫呋喃;d:反應使用的催化劑選自四氯合銅酸二鋰,溶劑選自四氫呋喃;e:反應使用的催化劑選自2,3-二氯-5,6-二氰對苯醌(DDQ),溶劑選自二氯甲烷,緩衝溶劑選自pH=7的磷酸鉀緩衝溶液;f:反應使用的氧化劑選自鄰碘醯苯甲酸(IBX),溶劑選自乙酸乙酯; g:反應使用的氧化體系選自2-甲基-2-丁烯/NaClO2/NaH2PO.2H2O,溶劑選自水和第三丁醇中的任一種或任幾種任意比例的混合物;h:反應使用的縮合試劑選自O-(7-氮雜苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽(HATU),鹼選自三乙胺,溶劑選自二氯甲烷;i:反應使用的酸酐為三氟甲磺酸酐,鹼為2,4,6-三甲基吡啶,進一步在鹼性條件下反應,所述的鹼為碳酸鉀。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein a: the hydroxyl protecting agent used in the reaction is selected from p-methoxybenzyl Chlorine, the base is selected from sodium hydride, the solvent is selected from tetrahydrofuran, the catalyst is selected from tetrabutylammonium iodide; b: the brominating reagent used in the reaction is selected from carbon tetrabromide, the solvent is selected from acetonitrile, and the catalyst is selected from triphenylphosphine c: the catalyst used in the reaction is selected from iodine, and the solvent used is selected from tetrahydrofuran; d: the catalyst used in the reaction is selected from dilithium tetrachlorocuprate, and the solvent is selected from tetrahydrofuran; e: the catalyst used in the reaction is selected from 2,3 -Dichloro-5,6-dicyano-p-benzoquinone (DDQ), the solvent is selected from dichloromethane, the buffer solvent is selected from potassium phosphate buffer solution with pH=7; f: the oxidant used in the reaction is selected from o-iodobenzoic acid (IBX), the solvent is selected from ethyl acetate; g: the oxidation system used in the reaction is selected from 2-methyl-2-butene/NaClO 2 /NaH 2 PO.2H 2 O, and the solvent is selected from water and tert-butanol Any one or any mixture in any ratio; h: the condensation reagent used in the reaction is selected from O-(7-azabenzotriazole-1-yl)-bis(dimethylamino)carbonium hexa Fluorophosphate (HATU), the base is selected from triethylamine, and the solvent is selected from dichloromethane; i: the acid anhydride used in the reaction is trifluoromethanesulfonic anhydride, and the base is 2,4,6-trimethylpyridine, and further in the base The reaction was carried out under neutral conditions, and the base was potassium carbonate.

本發明的一些具體實施例,一種式(I)所述化合物及其立體異構體或其藥學上可接受鹽的製備方法,其中a:以式(3-1)化合物為原料,與羥基保護劑反應製備得到式(3-2)化合物;反應使用的鹼選自氫化鈉、氫化鉀、碳酸鉀、碳酸鈉、碳酸銫、三乙胺、N,N-二異丙基乙胺或4-N,N-二甲基吡啶(DMAP);進一步反應使用的溶劑選自四氫呋喃、丙酮、乙醚、N-甲基吡咯烷酮、N,N-二甲基甲醯胺和甲苯中的任一種或任幾種任意比例的混合物;再進一步反應使用的催化劑選自四丁基碘化銨、碘化鈉、碘化鉀、溴化鈉、溴化鉀或四丁基溴化銨;b:以式(3-2)化合物為原料,與溴化試劑反應製備得到式(3-3)化合物;進一步所述的溴化試劑選自四溴化碳、氫溴酸、溴化鈉/硫酸、溴化氰、液溴、三溴化磷、1-丁基-3-甲基咪唑溴鹽或二溴海因;更進一步所述的催化劑選自膦類化合物,較佳為三苯基膦或三丁基膦等;再進一步反應使用的溶劑選自乙腈、二氯甲烷、水、四氫呋喃、甲苯、乙醚和乙酸乙酯中的任一種或任幾種任意比例的混合物;c:以式(3-3)化合物為原料,與金屬鎂反應製備得到式(3-4)化合物;進一步所述催化劑選自碘、1,2-二氯乙烷或異丙基溴化鎂;再進一步反應 使用的溶劑選自醚類溶劑,較佳為四氫呋喃或乙醚中的任一種或任幾種任意比例的混合物;d:以式(3-4)化合物為原料,與式(3-5)化合物製備得到式(3-6)化合物;進一步所述催化劑選自金屬試劑,較佳為四氯合銅酸二鋰、碘化亞銅、三氯化鈰、氯化鋰或二氯化鋅;更進一步反應使用的溶劑選自四氫呋喃,甲苯、二氧六環、乙醚、氯苯和二甲基亞碸中的任一種或任幾種任意比例的混合物;e:以式(3-6)化合物為原料,與脫保護反應製備得到式(3-7)化合物;進一步反應使用的催化劑選自2,3-二氯-5,6-二氰對苯醌(DDQ)、硝酸鈰銨、三氟甲烷磺酸鈰、Pd/C/H2、四氯化鋯;更進一步反應使用的緩衝溶劑選自pH=7的緩衝溶液,較佳為pH=7的磷酸鉀緩衝溶液或pH=7的磷酸鈉緩衝溶液;再進一步反應使用的溶劑選自二氯甲烷、乙腈、氯苯、甲苯、乙二醇二乙醚和硝基甲烷中的任一種或任幾種任意比例的混合物;f:以式(3-7)化合物為原料,與氧化劑反應製備得到式(3-8)化合物;進一步所述氧化劑選自鄰碘醯苯甲酸(IBX)、氯鉻酸吡啶鎓鹽(PCC)、三氧化硫吡啶、戴斯-馬丁氧化劑、瓊斯試劑、二甲基亞碸/草醯氯、TPAP([n-Pr4N][RuO4])/N-甲基嗎啉;更進一步反應使用的溶劑選自乙酸乙酯、二氯甲烷、丙酮和二甲基亞碸中的任一種或任幾種任意比例的混合物;g:以式(3-8)化合物為原料,與氧化劑反應製備得到式(3-9)化合物;進一步所述氧化劑選自NaClO2、重鉻酸吡啶嗡鹽(PDC)、高錳酸鉀、高碘酸鈉/三氯化釕、雙氧水/甲酸或二乙酸碘苯/2,2,6,6-四甲基呱啶氧化物,較佳為2-甲基-2-丁烯/NaClO2/NaH2PO4;更進一步反應使用的溶劑選自水、第三丁 醇、二氯甲烷、丙酮、二氧六環和甲苯中的任一種或任幾種任意比例的混合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein a: using the compound of formula (3-1) as a raw material, and protecting it with a hydroxyl group The compound of formula (3-2) is prepared by reacting with an agent; the base used in the reaction is selected from sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine or 4- N , N -lutidine (DMAP); the solvent used in the further reaction is selected from any one or several of tetrahydrofuran, acetone, diethyl ether, N-methylpyrrolidone, N,N-dimethylformamide and toluene A mixture in any proportion; the catalyst used in the further reaction is selected from tetrabutylammonium iodide, sodium iodide, potassium iodide, sodium bromide, potassium bromide or tetrabutylammonium bromide; b: with formula (3-2 ) compound is a raw material, and reacts with a brominating reagent to prepare a compound of formula (3-3); the further described brominating reagent is selected from carbon tetrabromide, hydrobromic acid, sodium bromide/sulfuric acid, cyanogen bromide, liquid bromine , phosphorus tribromide, 1-butyl-3-methylimidazolium bromide or dibromohydantoin; further the catalyst is selected from phosphine compounds, preferably triphenylphosphine or tributylphosphine, etc.; The solvent used for further reaction is selected from any one or any mixture of any ratio in acetonitrile, dichloromethane, water, tetrahydrofuran, toluene, ether and ethyl acetate; c: take the compound of formula (3-3) as a raw material , and react with metal magnesium to prepare the compound of formula (3-4); further the catalyst is selected from iodine, 1,2-dichloroethane or isopropyl magnesium bromide; the solvent used in the further reaction is selected from ether solvents , preferably any one of tetrahydrofuran or diethyl ether or a mixture of several arbitrary proportions; d: using the compound of formula (3-4) as a raw material, and the compound of formula (3-5) to prepare the compound of formula (3-6) Further, the catalyst is selected from metal reagents, preferably dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or zinc dichloride; the solvent used in the further reaction is selected from tetrahydrofuran, Any one of toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite or a mixture of any of several arbitrary proportions; e: take the compound of formula (3-6) as a raw material, and prepare the formula with deprotection reaction (3-7) Compound; the catalyst used in the further reaction is selected from 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), cerium ammonium nitrate, cerium trifluoromethanesulfonate, Pd/C/H 2. Zirconium tetrachloride; the buffer solvent used in the further reaction is selected from the buffer solution of pH=7, preferably the potassium phosphate buffer solution of pH=7 or the sodium phosphate buffer solution of pH=7; the solvent used in the further reaction be selected from any one or any mixture of any ratio in dichloromethane, acetonitrile, chlorobenzene, toluene, ethylene glycol diethyl ether and nitromethane; f: take the compound of formula (3-7) as a raw material, and an oxidant The compound of formula (3-8) is prepared by the reaction; further the oxidant is selected from o-iodobenzoic acid (IBX), pyridinium chlorochromate (PCC), sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, Dimethyl sulfite / oxalate Chlorine, TPAP([n-Pr 4 N][RuO 4 ])/N-methylmorpholine; the solvent used in the further reaction is selected from any of ethyl acetate, dichloromethane, acetone and dimethylsulfoxide. One or several mixtures in arbitrary proportions; g: take the compound of formula (3-8) as a raw material, and react with an oxidant to prepare a compound of formula (3-9); further, the oxidant is selected from NaClO 2 , pyridinium dichromate Salt (PDC), potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid or iodobenzene diacetate/2,2,6,6-tetramethylpyridine oxide, preferably 2- Methyl-2-butene/NaClO 2 /NaH 2 PO 4 ; the solvent used in the further reaction is selected from any one or several of water, tert-butanol, dichloromethane, acetone, dioxane and toluene a mixture of any proportion.

h:以式(3-9)化合物為原料,與吡咯烷在縮合劑存在下,在鹼性條件下反應製備得到式(3-10)化合物;進一步所述的縮合劑選自1-(3-二甲胺基丙基)-3-乙基碳二亞胺(EDCI)、羰基二咪唑(CDI)、二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)、甲烷磺醯氯(MsCl)、對甲苯磺醯氯(TsCl)、對硝基苯磺醯氯(NsCl)、O-(7-氮雜苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽(HATU)、O-(苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽(HBTU)、O-(5-氯苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽(HCTU)、O-(苯並三氮唑-1-基)-二(二甲胺基)碳鎓四氟硼酸鹽(TBTU)、O-(N-丁二醯亞胺基)-二(二甲胺基)碳鎓四氟硼酸鹽(TSTU)、O-(N-endo-5-降莰烯-2,3-二碳二醯亞胺)-二(二甲胺基)碳鎓四氟硼酸鹽(TNTU)、苯基磷醯氯(DPP-Cl)、氰代磷酸二乙酯(DECP)、疊氮化磷酸二苯酯(DPPA、硫代二甲基磷醯基疊氮(MPTA)或二(2-氧-3-唑烷基)磷醯氯(BOP-Cl);更進一步反應使用的鹼選自有機鹼或無機鹼,較佳為三乙胺、N,N-二異丙基乙胺、4-N,N-二甲基吡啶(DMAP)、1-羥基苯並三氮唑(HOBt)、碳酸鈉、碳酸鉀;再進一步反應使用的溶劑選自二氯甲烷、乙腈、乙酸乙酯、四氫呋喃、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二甲基亞碸和N-甲基吡咯烷酮中的任一種或任幾種任意比例的混合物;i:其中式(3-10)化合物在有機鹼存在下與酸酐或醯氯反應得到中間體亞胺鹽,然後再在鹼性條件下反應製備得到式(I)化合物;進一步所述的酸酐選自三氟甲磺酸酐或三氟乙酸酐;醯氯選自三氯氧磷、草醯氯、三光氣或氯化亞碸;所述有機鹼選自Collidine、2,4,6-三甲基吡啶、2-氟吡啶、2,6-二第三 丁基-4-甲基吡啶、2,6-二第三丁基吡啶、六甲基亞磷醯三胺、三乙胺、N,N-二異丙基乙胺或DBU(1,8-二氮雜雙環[5.4.0]十一碳-7-烯);所述的鹼選自無機鹼,較佳為金屬鹼,進一步較佳為碳酸鉀、碳酸鈉、碳酸銫、磷酸鉀、磷酸鈉、氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸氫鈉或碳酸氫鉀。 h: The compound of formula (3-9) is used as a raw material, and the compound of formula (3-10) is prepared by reacting with pyrrolidine in the presence of a condensing agent under basic conditions; further the condensing agent is selected from 1-(3 - Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), Carbonyldiimidazole (CDI), Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC) , Methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), p-nitrobenzenesulfonyl chloride (NsCl), O-(7-azabenzotriazol-1-yl)-bis(bis) Methylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5- Chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino) Carbonium tetrafluoroborate (TBTU), O-(N-butadiamido)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-nor Camphene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), phenylphosphonium chloride (DPP-Cl), diethyl cyanophosphate ( DECP), diphenylphosphoryl azide (DPPA, thiodimethylphosphoryl azide (MPTA), or bis(2-oxo-3-oxazolidinyl)phosphonium chloride (BOP-Cl); furthermore The base used in the reaction is selected from organic bases or inorganic bases, preferably triethylamine, N,N-diisopropylethylamine, 4- N , N -lutidine (DMAP), 1-hydroxybenzotrimine Azole (HOBt), sodium carbonate, potassium carbonate; the solvent used for further reaction is selected from dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylformamide Any one of acetamide, dimethyl sulfoxide and N-methylpyrrolidone or a mixture of any of several arbitrary proportions; i: wherein the compound of formula (3-10) reacts with acid anhydride or acyl chloride in the presence of an organic base to obtain The intermediate imide salt is then reacted under alkaline conditions to prepare the compound of formula (I); the acid anhydride is further selected from trifluoromethanesulfonic anhydride or trifluoroacetic anhydride; Acrylic chloride, triphosgene or sulfite chloride; the organic base is selected from Collidine, 2,4,6-collidine, 2-fluoropyridine, 2,6-di-tert-butyl-4-methylpyridine , 2,6-di-tert-butylpyridine, hexamethylphosphoric triamine, triethylamine, N,N-diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0 ]undec-7-ene); the base is selected from inorganic bases, preferably metal bases, further preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, hydroxide Sodium, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

本發明涉及一種製備式(I)所述化合物及其立體異構體或其藥學上可接受鹽的中間體,選自

Figure 108148250-A0305-02-0020-14
Figure 108148250-A0305-02-0020-15
Figure 108148250-A0305-02-0020-17
Figure 108148250-A0305-02-0020-18
;P選自羥基保護基,較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基;條件是P不為苄基或三氟乙基。 The present invention relates to an intermediate for preparing the compound of formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure 108148250-A0305-02-0020-14
,
Figure 108148250-A0305-02-0020-15
,
Figure 108148250-A0305-02-0020-17
or
Figure 108148250-A0305-02-0020-18
; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; Condition is P Not benzyl or trifluoroethyl.

除非有相反的陳述,在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated to the contrary, terms used in the specification and claims have the following meanings.

本發明涉及的通式化合物存在掌性中心時,除明確標示外,通式化合物可以是消旋體,也可以是旋光異構體。 When the compound of the general formula involved in the present invention has a chiral center, the compound of the general formula may be a racemate or an optical isomer unless clearly indicated.

本發明涉及到被多個取代基取代時,各取代基可以相同或不相同。 When the present invention relates to substitution with multiple substituents, each substituent may be the same or different.

本發明涉及到含有多個雜原子時,各雜原子可以相同或不相同。 When the present invention involves the inclusion of multiple heteroatoms, the heteroatoms may be the same or different.

本發明所述基團和化合物中所涉及的元素碳、氫、氧、硫、氮或鹵素均包括它們的同位素情況,及本發明所述基團和化合物中所涉及的元素碳、氫、氧、硫或氮任選進一步被1至5個它們對應的同位素所替代,其中碳的 同位素包括12C、13C和14C,氫的同位素包括氕(H)、氘(D,又叫重氫)、氚(T,又叫超重氫),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。 The elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopic conditions, and the elements carbon, hydrogen, oxygen involved in the groups and compounds of the present invention , sulfur or nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, also known as deuterium ), tritium (T, also known as super heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N , the isotope of fluorine is 19 F, the isotope of chlorine includes 35 Cl and 37 Cl, and the isotope of bromine includes 79 Br and 81 Br.

羥基保護基選自烷基醚類保護基、酯類保護基或矽醚類保護基,羥基保護基包括但不限於甲基、苄基、對甲氧基苄基、三苯甲基、第三丁基、甲氧基甲醚基、甲氧乙氧基甲基、四氫呋喃基、第三丁基羰基、苯甲醯基、乙醯基、氯甲基羰基、第三丁氧基羰基、苄氧基羰基、三甲基矽基、三乙基矽基、第三丁基二甲基矽基、第三丁基二苯基矽基、二第三丁基羥基矽基、對硝基苯甲醯基、烯丙基、苄氧基羰基、第三丁氧基羰基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基,較佳為甲基、S-(1-苯基)乙基氨基羰基或者R-(1-苯基)乙基氨基羰基。 The hydroxyl protecting group is selected from alkyl ether protecting groups, ester protecting groups or silyl ether protecting groups, and hydroxyl protecting groups include but are not limited to methyl, benzyl, p-methoxybenzyl, trityl, third Butyl, methoxymethyl ether, methoxyethoxymethyl, tetrahydrofuranyl, tert-butylcarbonyl, benzyl, acetyl, chloromethylcarbonyl, tert-butoxycarbonyl, benzyloxy Carbonyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, di-tert-butylhydroxysilyl, p-nitrobenzyl group, allyl, benzyloxycarbonyl, tertiary butoxycarbonyl, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl, preferably methyl, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl.

烷基醚類保護基可以在鹼性或酸性條件下脫除,所述鹼或酸包括但不限於氫化鈉、甲醇鈉、碳酸鉀、氫氧化鉀、氫氧化鈉、吡啶、三氟乙酸、鹽酸、甲酸或乙酸;酯類保護基可以在鹼性條件下脫除,所述鹼包括但不限於甲醇鈉、碳酸鉀、氫氧化鉀、氫氧化鈉、氫化鋁鋰、吡啶或氨;矽醚類保護基可以在氟化氫、四丁基氟化氨等條件下脫除。 Alkyl ether protecting groups can be removed under basic or acidic conditions, the bases or acids include but are not limited to sodium hydride, sodium methoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, pyridine, trifluoroacetic acid, hydrochloric acid , formic acid or acetic acid; ester protecting groups can be removed under alkaline conditions, the bases include but are not limited to sodium methoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, pyridine or ammonia; silyl ethers The protecting group can be removed under conditions such as hydrogen fluoride, tetrabutylammonium fluoride and the like.

羥基保護劑一般為羥基保護基的醯鹵、鹵代或鹵化物;包括但不限於對甲氧基苄氯、碘甲烷、氯甲基甲醚、第三丁基二甲基氯化矽、第三丁基二苯基氯化矽、苄溴。 Hydroxyl protecting agents are generally halides, halogens or halides of hydroxyl protecting groups; including but not limited to p-methoxybenzyl chloride, methyl iodide, chloromethyl methyl ether, tert-butyldimethylsilicon chloride, Tributyldiphenylsilicon chloride, benzyl bromide.

PMB:對甲氧基苄基。 PMB: p-methoxybenzyl.

以下通過具體實施例詳細說明本發明的實施過程和產生的有益效果,旨在幫助閱讀者更好地理解本發明的實質和特點,不作為對本案可實施範圍的限定。 The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present case.

化合物的結構是通過核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10-6(ppm)的單位表示。NMR的測定是用(BrukerAvance III 400和BrukerAvance 300)核磁儀,測定溶劑為氘代二甲基亞碸(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),氘代乙腈(CD3CN),內標為四甲基矽烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are expressed in units of 10 −6 (ppm). NMR was measured using (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetic instruments, and the solvents were deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), Deuterated acetonitrile (CD 3 CN), the internal standard is tetramethylsilane (TMS).

MS的測定用Agilent 6120B(ESI)和Agilent 6120B(APCI)。 For MS measurement, Agilent 6120B (ESI) and Agilent 6120B (APCI) were used.

HPLC的測定使用安捷倫1260DAD高壓液相層析儀(Zorbax SB-C18 100×4.6mm)。 For the HPLC measurement, an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm) was used.

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板,薄層層析法(TLC)使用的矽膠板採用的規格是0.15mm~0.20mm,薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm, and the specification used for TLC separation and purification products is 0.4 mm~0.5mm.

管柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

本發明的已知的起始原料可以採用或按照本領域已知的方法來合成,或可購買於泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、百靈威科技等公司。 The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.

本發明矽膠柱層析所示比例為體積比。 The ratio shown in the silica gel column chromatography of the present invention is the volume ratio.

實施例1Example 1

Figure 108148250-A0305-02-0023-19
Figure 108148250-A0305-02-0023-19

第一步 first step

4-[(4-methoxyphenyl)methoxy]butan-1-ol 4-[(4-methoxyphenyl)methoxy]butan-1-ol

4-[(4-甲氧基苯基)甲氧基]丁基-1-醇(化合物3-2) 4-[(4-Methoxyphenyl)methoxy]butyl-1-ol (Compound 3-2 )

Figure 108148250-A0305-02-0023-20
Figure 108148250-A0305-02-0023-20

0℃下,將1,4-丁二醇3-1(100mL,1.1mol)逐滴滴加到氫化鈉(142.3g,1.1mol)的四氫呋喃(1L)懸浮液中,加畢,攪拌10min,接著向反應體系中加入四丁基碘化銨(46g,114mmol)和對甲氧基苄氯(155mL,1.14mol),保持0℃反應30min,升溫至室溫反應17h停止反應。向反應液中加入飽和碳酸氫鈉溶液(300mL)淬滅反應,使用乙酸乙酯(350mL x 3)萃取有機相,合併有機相,使用無水硫酸鈉乾燥,減壓除去溶劑,管柱層析分離(石油醚/乙酸乙酯=1:1)得到化合物3-2(186g,69.3%),化合物3-2為無色液體。 At 0 °C, 1,4-butanediol 3-1 (100 mL, 1.1 mol) was added dropwise to a suspension of sodium hydride (142.3 g, 1.1 mol) in tetrahydrofuran (1 L), the addition was completed, and stirred for 10 min, Then, tetrabutylammonium iodide (46 g, 114 mmol) and p-methoxybenzyl chloride (155 mL, 1.14 mol) were added to the reaction system, kept at 0° C. for 30 min, and the temperature was raised to room temperature for 17 h to stop the reaction. Saturated sodium bicarbonate solution (300 mL) was added to the reaction solution to quench the reaction, the organic phase was extracted with ethyl acetate (350 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and separated by column chromatography (Petroleum ether/ethyl acetate=1:1) to obtain compound 3-2 (186 g, 69.3%), which is a colorless liquid.

1H NMR(400MHz,Chloroform-d)δ 7.25(d,J=8.7Hz,2H),6.92-6.83(m,2H),4.45(d,J=1.2Hz,2H),3.80d,J=1.3Hz,3H),3.63(ddd,J=7.8,4.4,1.6Hz,2H),3.49(td,J=5.8,1.3Hz,2H),2.04(d,J=0.9Hz,1H),1.26(td,J=7.1,0.9Hz,1H). 1 H NMR (400MHz, Chloroform- d )δ 7.25(d, J =8.7Hz, 2H), 6.92-6.83(m, 2H), 4.45(d, J =1.2Hz, 2H), 3.80d, J =1.3 Hz,3H),3.63(ddd, J =7.8,4.4,1.6Hz,2H),3.49(td, J =5.8,1.3Hz,2H),2.04(d, J =0.9Hz,1H),1.26(td , J =7.1,0.9Hz,1H).

第二步 second step

1-(4-bromobutoxymethyl)-4-methoxy-benzene 1-(4-bromobutoxymethyl)-4-methoxy-benzene

1-(4-溴丁氧基甲基)-4-甲氧基-苯(化合物3-3) 1-(4-Bromobutoxymethyl)-4-methoxy-benzene (compound 3-3 )

Figure 108148250-A0305-02-0024-21
Figure 108148250-A0305-02-0024-21

將4-[(4-甲氧基苯基)甲氧基]丁基-1-醇3-2(186g,762mmol)溶解在乙腈(700mL)和二氯甲烷(300mL)的混合溶劑中,冷卻至0℃,向反應液中加入三苯基膦(301.9g,1.2mol),接著分批向反應體系中加入四溴化碳(381.6g,1.2mol)。反應結束後,過濾除去不溶物,減壓除去反應溶劑,進行管柱層析(石油醚/乙酸乙酯=50:1~5:1)分離得到化合物3-3(240g,99.6%)。 4-[(4-Methoxyphenyl)methoxy]butyl-1-ol 3-2 (186 g, 762 mmol) was dissolved in a mixed solvent of acetonitrile (700 mL) and dichloromethane (300 mL), and cooled To 0°C, triphenylphosphine (301.9 g, 1.2 mol) was added to the reaction solution, followed by addition of carbon tetrabromide (381.6 g, 1.2 mol) to the reaction system in portions. After the reaction, the insolubles were removed by filtration, the reaction solvent was removed under reduced pressure, and column chromatography (petroleum ether/ethyl acetate=50:1~5:1) was performed to isolate compound 3-3 (240 g, 99.6%).

1H NMR(400MHz,Chloroform-d)δ 7.24(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),4.42(s,2H),3.79(s,3H),3.44(dt,J=20.8,6.5Hz,4H),2.02-1.89(m,2H),1.80-1.67(m,2H). 1 H NMR (400MHz, Chloroform- d )δ 7.24(d, J =8.6Hz, 2H), 6.87(d, J =8.6Hz, 2H), 4.42(s, 2H), 3.79(s, 3H), 3.44 (dt, J =20.8,6.5Hz,4H),2.02-1.89(m,2H),1.80-1.67(m,2H).

第三步 third step

bromo-[4-[(4-methoxyphenyl)methoxy]butyl]magnesium bromo-[4-[(4-methoxyphenyl)methoxy]butyl]magnesium

溴-[4-[(4-甲氧基苯基)甲氧基]丁基]鎂鹽(化合物3-4) Bromo-[4-[(4-methoxyphenyl)methoxy]butyl]magnesium salt (compound 3-4 )

Figure 108148250-A0305-02-0024-22
Figure 108148250-A0305-02-0024-22

將經過活化的鎂屑(1.05g,43.8mmol)置於10mL三口燒瓶中,加入磁攪拌子和一粒碘,氮氣置換三次,注入6mL無水四氫呋喃,滴入4-[(4-甲氧基苯基)甲氧基]丁基-1-醇(化合物3-3)(1g,3.7mmol),攪拌情況下,緩慢加熱,直至格氏試劑引發完成(可以明顯地觀察到反應液顏色由棕色變為無色),接著緩慢滴加25mL的1-(4-溴丁氧基甲基)-4-甲氧基-苯(化合物3-3)(9g,33mmol)四氫呋喃溶液,滴加過程使反應處於微沸狀態,約30min加完,加完繼續回流反應1h。冷卻至室溫,注射器抽出上層清液共20mL格氏試劑待用。 The activated magnesium chips (1.05g, 43.8mmol) were placed in a 10mL three-necked flask, a magnetic stirrer and a grain of iodine were added, nitrogen was replaced three times, 6mL of anhydrous tetrahydrofuran was injected, and 4-[(4-methoxybenzene was added dropwise. yl)methoxy]butyl-1-ol (compound 3-3 ) (1 g, 3.7 mmol), under stirring, slowly heated until the initiation of Grignard reagent is completed (it can be clearly observed that the color of the reaction solution changes from brown to was colorless), then slowly added dropwise 25 mL of 1-(4-bromobutoxymethyl)-4-methoxy-benzene (compound 3-3 ) (9 g, 33 mmol) tetrahydrofuran solution, the dropwise addition process made the reaction in In a slightly boiling state, the addition was completed in about 30 minutes, and the reflux reaction was continued for 1 hour after the addition. After cooling to room temperature, a total of 20 mL of Grignard reagent was withdrawn from the supernatant with a syringe.

第四步(方法A) Step 4 (Method A)

1-(4-(cyclopent-3-en-1-yl)butoxymethyl)-4-methoxy-benzene 1-(4-(cyclopent-3-en-1-yl)butoxymethyl)-4-methoxy-benzene

1-(4-(環戊基-3-烯-1-基)丁氧基甲基)-4-甲氧基-苯(化合物3-6) 1-(4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 )

Figure 108148250-A0305-02-0025-23
Figure 108148250-A0305-02-0025-23

將(化合物3-5)(0.45g,1.90mmol)置於50mL三口燒瓶中,氮氣置換三次,加入10mL無水四氫呋喃,乾冰乙醇冷卻至-78℃,緩慢滴加四氯合銅酸二鋰(2.0mL,0.1M),加完繼續攪拌0.5h,接著緩慢滴加格氏試劑3-4(2.7mL,5mmol),(實驗現象由深棕變淡藍色)加完繼續-78℃反應1h,升至-20℃反應3h,然後室溫過夜,次日加入5mL飽和氯化銨溶液淬滅反應,加入15mL甲基第三丁基醚,萃取分離有機相,再用30mL甲基第三丁基醚分兩次對水相進行反萃,合併有機相,無水硫酸鈉乾燥,過濾,減壓濃縮,粗產物經管柱層析分離純化,得粗品600mg,經高效液相製備分離得到1-(4-(環戊基-3-烯-1-基)丁氧基甲基)-4-甲氧基-苯(化合物3-6)(150mg,30%)。 (Compound 3-5 ) (0.45 g, 1.90 mmol) was placed in a 50 mL three-necked flask, nitrogen was replaced three times, 10 mL of anhydrous tetrahydrofuran was added, dry ice ethanol was cooled to -78 ° C, and dilithium tetrachlorocuprate (2.0 mL, 0.1M), continue to stir for 0.5h after the addition, and then slowly dropwise add Grignard reagent 3-4 (2.7mL, 5mmol), (the experimental phenomenon changes from dark brown to light blue) and continue to react at -78°C for 1h, The reaction was heated to -20 °C for 3 hours, then overnight at room temperature. The next day, 5 mL of saturated ammonium chloride solution was added to quench the reaction, 15 mL of methyl tert-butyl ether was added, and the organic phase was extracted and separated, and then 30 mL of methyl tertiary butyl ether was added. The aqueous phase was back-extracted twice with ether, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain 600 mg of crude product, which was prepared and separated by high performance liquid phase to obtain 1-(4 -(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 ) (150 mg, 30%).

1H NMR(400MHz,CDCl3)δ 7.26(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),5.65(s,2H),4.43(s,2H),3.80(s,3H),3.44(t,J=6.6Hz,2H),2.53-2.38(m,2H),2.21(dd,J=10.9,4.1Hz,1H),1.94(dd,J=13.7,6.6Hz,2H),1.74-1.51(m,2H),1.47-1.27(m,4H). 1 H NMR (400MHz, CDCl 3 )δ 7.26(d, J =8.6Hz, 2H), 6.87(d, J =8.6Hz, 2H), 5.65(s, 2H), 4.43(s, 2H), 3.80( s, 3H), 3.44(t, J =6.6Hz, 2H), 2.53-2.38(m, 2H), 2.21(dd, J =10.9, 4.1Hz, 1H), 1.94(dd, J =13.7, 6.6Hz ,2H),1.74-1.51(m,2H),1.47-1.27(m,4H).

第四步(方法B) Step 4 (Method B)

1-(4-(cyclopent-3-en-1-yl)butoxymethyl)-4-methoxy-benzene 1-(4-(cyclopent-3-en-1-yl)butoxymethyl)-4-methoxy-benzene

1-(4-(環戊基-3-烯-1-基)丁氧基甲基)-4-甲氧基-苯(化合物3-6) 1-(4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 )

Figure 108148250-A0305-02-0025-24
Figure 108148250-A0305-02-0025-24

將(化合物3-5)(7.1g,30.0mmol)置於500mL三口燒瓶中,氮氣置換三次,加入150mL無水四氫呋喃,乾冰乙醇冷卻至-78℃,緩慢滴加四氯合銅酸二鋰(31.6mL,0.1M),加完繼續攪拌0.5h,接著緩慢滴加格氏試劑3-4(19.4mL,36mmol),(實驗現象由深棕變淡藍色)加完繼續-78℃反應1h,升至-20℃反應3h,然後室溫過夜,次日加入50mL飽和氯化銨溶液淬滅反應,加入150mL甲基第三丁基醚,萃取分離有機相,再用300mL甲基第三丁基醚分兩次對水相進行反萃,合併有機相,無水硫酸鈉乾燥,過濾,減壓濃縮,粗產物經管柱層析分離純化,得粗品5.8g,經高效液相製備分離得到1-(4-(環戊基-3-烯-1-基)丁氧基甲基)-4-甲氧基-苯(化合物3-6)(1.5g,19%)。 (Compound 3-5 ) (7.1 g, 30.0 mmol) was placed in a 500 mL three-necked flask, nitrogen was replaced three times, 150 mL of anhydrous tetrahydrofuran was added, dry ice ethanol was cooled to -78 ° C, and dilithium tetrachlorocuprate (31.6 mL, 0.1M), continue to stir for 0.5h after the addition, and then slowly dropwise add Grignard reagent 3-4 (19.4mL, 36mmol), (the experimental phenomenon changed from dark brown to light blue) and continue to react at -78°C for 1h, The reaction was heated to -20°C for 3 hours, then overnight at room temperature. The next day, 50 mL of saturated ammonium chloride solution was added to quench the reaction, 150 mL of methyl tert-butyl ether was added, and the organic phase was extracted and separated, and then 300 mL of methyl tert-butyl ether was added. The aqueous phase was back-extracted with ether in two times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain a crude product of 5.8 g, which was prepared and separated by high performance liquid phase to obtain 1-( 4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 ) (1.5 g, 19%).

1H NMR(400MHz,CDCl3)δ 7.26(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),5.65(s,2H),4.43(s,2H),3.80(s,3H),3.44(t,J=6.6Hz,2H),2.53-2.38(m,2H),2.21(dd,J=10.9,4.1Hz,1H),1.94(dd,J=13.7,6.6Hz,2H),1.741.51(m,2H),1.47-1.27(m,4H). 1 H NMR (400MHz, CDCl 3 )δ 7.26(d, J =8.6Hz, 2H), 6.87(d, J =8.6Hz, 2H), 5.65(s, 2H), 4.43(s, 2H), 3.80( s, 3H), 3.44(t, J =6.6Hz, 2H), 2.53-2.38(m, 2H), 2.21(dd, J =10.9, 4.1Hz, 1H), 1.94(dd, J =13.7, 6.6Hz ,2H),1.741.51(m,2H),1.47-1.27(m,4H).

第五步 the fifth step

4-(cyclopent-3-en-1-yl)butan-1-ol 4-(cyclopent-3-en-1-yl)butan-1-ol

4-(環戊基-3-烯-1-基)丁基-1-醇(化合物3-7) 4-(Cyclopentyl-3-en-1-yl)butyl-1-ol (Compound 3-7 )

Figure 108148250-A0305-02-0026-25
Figure 108148250-A0305-02-0026-25

將1-(4-(環戊基-3-烯-1-基)丁氧基甲基)-4-甲氧基-苯(化合物3-6)(135mg,0.52mmol)置於25mL圓底燒瓶中,加入4.5mL二氯甲烷和pH=7的磷酸鉀緩衝溶液(0.5mL),加入DDQ(147mg,0.65mmol),室溫下反應1h。TLC檢測,反應完全,加入5mL的碳酸氫鈉飽和溶液和硫代硫酸鈉飽和溶液(體積比為1:1)淬滅反應,分離有機相,用30mL的二氯甲烷分三次對水相進行 反萃,合併有機相,無水硫酸鈉乾燥。過濾,室溫減壓濃縮,粗產物經管柱層析分離純化,沖提劑為PE/EA=4/1,得到目標產物4-(環戊基-3-烯-1-基)丁基-1-醇(化合物3-7)為無色液體(70mg,96%)。 1-(4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 ) (135 mg, 0.52 mmol) was placed in a 25 mL round bottom In the flask, add 4.5 mL of dichloromethane and potassium phosphate buffer solution (0.5 mL) of pH=7, add DDQ (147 mg, 0.65 mmol), and react at room temperature for 1 h. TLC detected, the reaction was complete, 5 mL of saturated sodium bicarbonate solution and saturated sodium thiosulfate solution (volume ratio of 1:1) were added to quench the reaction, the organic phase was separated, and the aqueous phase was reversed with 30 mL of dichloromethane three times. Extract, combine the organic phases, and dry over anhydrous sodium sulfate. Filtration, concentrated under reduced pressure at room temperature, the crude product was separated and purified by column chromatography, and the eluent was PE/EA=4/1 to obtain the target product 4-(cyclopentyl-3-en-1-yl)butyl- 1-ol (compound 3-7 ) was a colorless liquid (70 mg, 96%).

1H NMR(400MHz,CDCl3)δ 5.66(s,2H),3.65(t,J=6.6Hz,2H),2.57-2.38(m,2H),2.28-2.14(m,1H),1.96(dd,J=13.6,6.6Hz,2H),1.63-1.53(m,2H),1.50(s,1H),1.46-1.33(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 5.66 (s, 2H), 3.65 (t, J = 6.6 Hz, 2H), 2.57-2.38 (m, 2H), 2.28-2.14 (m, 1H), 1.96 (dd , J =13.6,6.6Hz,2H),1.63-1.53(m,2H),1.50(s,1H),1.46-1.33(m,4H).

第六步 Step 6

4-(cyclopent-3-en-1-yl)butanal 4-(cyclopent-3-en-1-yl)butanal

4-(環戊基-3-烯-1-基)丁醛(化合物3-8) 4-(Cyclopentyl-3-en-1-yl)butanal (Compound 3-8 )

Figure 108148250-A0305-02-0027-26
Figure 108148250-A0305-02-0027-26

將4-(環戊基-3-烯-1-基)丁基-1-醇(化合物3-7)(25mg,0.18mmol)置於25mL圓底燒瓶中,加入6mL乙酸乙酯,加入IBX(76mg,0.27mmol),攪拌下回流反應4小時。TLC檢測大部分原料消失,用硝基苯肼顯色產物點為淡黃色,冷卻至室溫,用砂芯漏斗濾去不溶物,並用5mL乙酸乙酯洗滌濾渣,收集濾液,20℃下小心減壓除去大部分溶劑,粗產物4-(環戊基-3-烯-1-基)丁醛(化合物3-8)直接用於下一步反應。 4-(Cyclopentyl-3-en-1-yl)butyl-1-ol (compound 3-7 ) (25 mg, 0.18 mmol) was placed in a 25 mL round bottom flask, 6 mL of ethyl acetate was added, and IBX was added (76 mg, 0.27 mmol), and the reaction was refluxed for 4 hours with stirring. TLC detected that most of the raw materials disappeared, and the product was light yellow with nitrophenylhydrazine, cooled to room temperature, filtered off with a sand core funnel, and the filter residue was washed with 5 mL of ethyl acetate. Most of the solvent was removed under pressure, and the crude product 4-(cyclopentyl-3-en-1-yl)butanal (compound 3-8 ) was directly used in the next reaction.

第七步 Step 7

4-(cyclopent-3-en-1-yl)butanoic acid 4-(cyclopent-3-en-1-yl)butanoic acid

4-(環戊基-3-烯-1-基)丁酸(化合物3-9) 4-(Cyclopentyl-3-en-1-yl)butanoic acid (compound 3-9 )

Figure 108148250-A0305-02-0027-27
Figure 108148250-A0305-02-0027-27

將粗產物4-(環戊基-3-烯-1-基)丁醛(化合物3-8)(25mg,0.18mmol)置於25mL圓底燒瓶中,加入5mL第三丁醇和水的混合溶劑(體積比為 3/1),降至0℃,加入2-甲基-2-丁烯(0.4mL,3.8mmol),NaClO2(48mg,0.54mmol)和NaH2PO4.2H2O(140mg,0.9mmol),並繼續攪拌1小時,TLC檢測,原料反應完全,加入5mL硫代硫酸鈉飽和溶液淬滅反應,加入20mL乙酸乙酯,萃取分離有機相,再用30mL二氯甲烷分兩次對水相進行反萃,合併有機相,無水硫酸鈉乾燥,過濾,室溫減壓濃縮,粗產物經管柱層析分離純化,沖提劑為PE/EA(4/1-2/1),分離得到4-(環戊基-3-烯-1-基)丁酸(化合物3-9)(18mg,65%) The crude product 4-(cyclopentyl-3-en-1-yl)butanal (compound 3-8 ) (25 mg, 0.18 mmol) was placed in a 25 mL round bottom flask, and 5 mL of a mixed solvent of tertiary butanol and water was added (3/1 by volume), lowered to 0°C, added 2-methyl-2-butene (0.4 mL, 3.8 mmol), NaClO 2 (48 mg, 0.54 mmol) and NaH 2 PO 4 . 2H 2 O (140 mg, 0.9 mmol), and continued to stir for 1 hour, TLC detected that the reaction of the raw materials was complete, 5 mL of saturated sodium thiosulfate solution was added to quench the reaction, 20 mL of ethyl acetate was added, and the organic phase was extracted and separated. The aqueous phase was back-extracted with methyl chloride twice, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at room temperature. The crude product was separated and purified by column chromatography, and the eluent was PE/EA (4/1- 2/1), isolated to obtain 4-(cyclopentyl-3-en-1-yl)butanoic acid (compound 3-9 ) (18mg, 65%)

1H NMR(400MHz,CDCl3)δ 5.66(s,2H),2.48(dd,J=14.1,8.7Hz,2H),2.40-2.31(m,2H),2.30-2.18(m,1H),1.97(dd,J=13.7,6.4Hz,2H),1.66(dt,J=12.2,7.5Hz,2H),1.51-1.39(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 5.66 (s, 2H), 2.48 (dd, J = 14.1, 8.7 Hz, 2H), 2.40-2.31 (m, 2H), 2.30-2.18 (m, 1H), 1.97 (dd, J =13.7,6.4Hz,2H),1.66(dt, J =12.2,7.5Hz,2H),1.51-1.39(m,2H).

第八步 Step 8

4-(cyclopent-3-en-1-yl)-1-(pyrrolidin-1-yl)butan-1-one 4-(cyclopent-3-en-1-yl)-1-(pyrrolidin-1-yl)butan-1-one

4-(環戊基-3-烯-1-基)-1-(吡咯-1-基)丁基-1-酮(化合物3-10) 4-(Cyclopentyl-3-en-1-yl)-1-(pyrrol-1-yl)butyl-1-one (Compound 3-10 )

Figure 108148250-A0305-02-0028-28
Figure 108148250-A0305-02-0028-28

將(化合物3-9)(0.50g,3.20mol)用二氯甲烷(25mL)溶解後,0℃下依次加入三乙胺(0.82g,8.10mol),HATU(1.80g,4.90mol)。緩慢滴加吡咯烷(0.35g,4.90mol),加畢,升溫到室溫反應10小時。TLC監測反應完全,加入水(200mL x 2)洗滌。分離有機層,依次用NH4Cl溶液(200mL x 2)洗滌,再用飽和食鹽水(200mL x 2)洗滌;無水硫酸鈉乾燥,過濾,將濾液減壓濃縮,管柱層析後得中間體(化合物3-10)(0.40g,60%)。 After (compound 3-9 ) (0.50 g, 3.20 mol) was dissolved in dichloromethane (25 mL), triethylamine (0.82 g, 8.10 mol) and HATU (1.80 g, 4.90 mol) were sequentially added at 0°C. Pyrrolidine (0.35 g, 4.90 mol) was slowly added dropwise, the addition was completed, and the temperature was raised to room temperature to react for 10 hours. The reaction was complete as monitored by TLC, and water (200 mL x 2) was added to wash. The organic layer was separated, washed successively with NH 4 Cl solution (200 mL×2), and then with saturated brine (200 mL×2); dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the intermediate was obtained after column chromatography (Compound 3-10 ) (0.40 g, 60%).

第九步 Step 9

(±)-(1R,3S,6R,8R)-tricyclo[4.2.1.03,8]nonan-2-one (±)-(1R,3S,6R,8R)-tricyclo[4.2.1.03,8]nonan-2-one

(±)-(1R,3S,6R,8R)-三環[4.2.1.03,8]壬烷-2-酮(化合物I) (±)-(1R,3S,6R,8R)-tricyclo[4.2.1.03,8]nonan-2-one (Compound I )

Figure 108148250-A0305-02-0029-29
Figure 108148250-A0305-02-0029-29

將化合物3-10(0.30g,1.4mol)用二氯甲烷(10mL)溶解後,加入2,4,6-三甲基吡啶(0.19g,1.70mol)。0℃下,將三氟甲磺酸酐(0.61g,2.2mol),溶於2mL二氯甲烷中,緩慢滴加到反應液中。加畢,升溫到50℃回流反應5小時。LCMS監測反應完全,減壓濃縮,得中間體亞胺鹽。 After compound 3-10 (0.30 g, 1.4 mol) was dissolved in dichloromethane (10 mL), 2,4,6-collidine (0.19 g, 1.70 mol) was added. At 0°C, trifluoromethanesulfonic anhydride (0.61 g, 2.2 mol) was dissolved in 2 mL of dichloromethane, and slowly added dropwise to the reaction solution. After the addition was completed, the temperature was raised to 50°C and the reaction was refluxed for 5 hours. The reaction was monitored by LCMS and concentrated under reduced pressure to obtain the intermediate imide salt.

將中間體亞胺鹽溶於水和丙酮的混合溶劑(8mL,v/v=1:1),向體系加入碳酸鉀(0.97g,7mol),升溫到回流反應3小時,TLC監測反應(DCM/MeOH=15:1)至反應完全,加入1M HCl調pH約為2-3,用甲基第三丁基醚萃取(20mL×3)反應液,合併有機相,無水硫酸鈉乾燥,減壓濃縮除去溶劑,粗產物快速管柱層析(PE/EA=20:1)得白色固體產物(化合物I)(0.12g,60%易揮發)。 The intermediate imide salt was dissolved in a mixed solvent of water and acetone (8 mL, v/v=1:1), potassium carbonate (0.97 g, 7 mol) was added to the system, the temperature was raised to reflux for 3 hours, and the reaction was monitored by TLC (DCM /MeOH=15:1) until the reaction is complete, add 1M HCl to adjust the pH to about 2-3, extract the reaction solution with methyl tert-butyl ether (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and reduce the pressure. The solvent was removed by concentration, and the crude product was subjected to flash column chromatography (PE/EA=20:1) to obtain a white solid product (compound I ) (0.12 g, 60% volatile).

1H NMR(400MHz,CDCl3)δ 3.51-3.28(m,1H),3.27-3.05(m,1H),2.89-2.66(m,1H),2.47-2.25(m,1H),2.12-1.97(m,1H),1.93(d,J=12.2Hz,1H),1.85-1.61(m,1H),1.62-1.32(m,4H),1.21(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ 3.51-3.28(m,1H), 3.27-3.05(m,1H), 2.89-2.66(m,1H), 2.47-2.25(m,1H), 2.12-1.97( m, 1H), 1.93 (d, J = 12.2Hz, 1H), 1.85-1.61 (m, 1H), 1.62-1.32 (m, 4H), 1.21 (m, 1H).

Figure 108148250-A0101-11-0001-2
Figure 108148250-A0101-11-0001-2

Claims (31)

一種式(I)所示稠合三環衍生物及其立體異構體或其藥學上可接受鹽的製備方法,其特徵在於是通過式(3-10)化合物製備得到;
Figure 108148250-A0305-02-0030-31
式(3-10)化合物在鹼的條件下與酸酐或醯氯反應,所述的酸酐選自三氟甲磺酸酐或三氟乙酸酐;所述的醯氯選自三氯氧磷、草醯氯、三光氣或氯化亞碸;所述的鹼選自有機鹼。
A preparation method of a fused tricyclic derivative represented by formula (I) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is prepared from a compound of formula (3-10);
Figure 108148250-A0305-02-0030-31
The compound of formula (3-10) reacts with acid anhydride or acyl chloride under the condition of alkali, and the acid anhydride is selected from trifluoromethanesulfonic anhydride or trifluoroacetic anhydride; the acyl chloride is selected from phosphorus oxychloride, oxalic acid Chlorine, triphosgene or thionous chloride; the base is selected from organic bases.
根據請求項1所述的製備方法,其中,所述的鹼為Collidine、2,4,6-三甲基吡啶、2-氟吡啶、2,6-二第三丁基-4-甲基吡啶、2,6-二第三丁基吡啶、六甲基亞磷醯三胺、三乙胺、N,N-二異丙基乙胺或DBU。 The preparation method according to claim 1, wherein the base is Collidine, 2,4,6-trimethylpyridine, 2-fluoropyridine, 2,6-di-tert-butyl-4-methylpyridine , 2,6-di-tert-butylpyridine, hexamethylphosphoric triamine, triethylamine, N,N-diisopropylethylamine or DBU. 根據請求項1所述的製備方法,其中進一步在鹼性條件下反應,所述的鹼選自無機鹼。 The preparation method according to claim 1, wherein the reaction is further performed under alkaline conditions, and the base is selected from inorganic bases. 根據請求項3所述的製備方法,所述的鹼為金屬鹼。 According to the preparation method of claim 3, the base is a metal base. 根據請求項3所述的製備方法,所述的鹼為碳酸鉀、碳酸鈉、碳酸銫、磷酸鉀、磷酸鈉、氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸氫鈉或碳酸氫鉀。 According to the preparation method described in claim 3, the alkali is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. 根據請求項1所述的製備方法,其中還包括通過式(3-9)化合物製備得到式(3-10)化合物,
Figure 108148250-A0305-02-0030-32
式(3-9)化合物、吡咯烷、縮合劑在鹼性條件下反應製備得到式(3-10)化合物。
The preparation method according to claim 1, further comprising preparing the compound of formula (3-10) by preparing the compound of formula (3-9),
Figure 108148250-A0305-02-0030-32
The compound of formula (3-9), pyrrolidine and condensing agent are reacted under basic conditions to prepare the compound of formula (3-10).
根據請求項6所述的製備方法,其中,所述的縮合劑選自1-(3-二甲胺基丙基)-3-乙基碳二亞胺、羰基二咪唑、二環己基碳二亞胺、二異丙基碳二亞胺、甲烷磺醯氯、對甲苯磺醯氯、對硝基苯磺醯氯、O-(7-氮雜苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽、O-(苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽、O-(5-氯苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽、O-(苯並三氮唑-1-基)-二(二甲胺基)碳鎓四氟硼酸鹽、O-(N-丁二醯亞胺基)-二(二甲胺基)碳鎓四氟硼酸鹽、O-(N-endo-5-降莰烯-2,3-二碳二醯亞胺)-二(二甲胺基)碳鎓四氟硼酸鹽、苯基磷醯氯、氰代磷酸二乙酯、疊氮化磷酸二苯酯、硫代二甲基磷醯基疊氮或二(2-氧-3-唑烷基)磷醯氯;反應使用的鹼選自有機鹼或無機鹼;反應使用的溶劑選自二氯甲烷、乙腈、乙酸乙酯、四氫呋喃、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二甲基亞碸和N-甲基吡咯烷酮中的任一種或任幾種任意比例的混合物。 The preparation method according to claim 6, wherein the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide Imine, diisopropylcarbodiimide, methanesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, O-(7-azabenzotriazol-1-yl)-di (Dimethylamino)carbonium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(5-chlorobenzotriazole) Azol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-Butanediimido)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-endo-5-norbornene-2,3-dicarbodiimide )-bis(dimethylamino)carbonium tetrafluoroborate, phenylphosphonium chloride, diethyl cyanophosphate, diphenylphosphoric azide, thiodimethylphosphonium azide or bis( 2-oxo-3-oxazolidinyl) phosphonium chloride; the base used in the reaction is selected from organic bases or inorganic bases; the solvent used in the reaction is selected from dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformaldehyde Any one or a mixture of any of several in any ratio of carboxymethyl amide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone. 根據請求項7所述的製備方法,其中,反應使用的鹼為三乙胺、N,N-二異丙基乙胺、4-N,N-二甲基吡啶、1-羥基苯並三氮唑、碳酸鈉或碳酸鉀。 The preparation method according to claim 7, wherein the base used in the reaction is triethylamine, N,N-diisopropylethylamine, 4- N , N -lutidine, 1-hydroxybenzotriazepine azole, sodium carbonate or potassium carbonate. 根據請求項6所述的製備方法,其中還包括通過式(3-8)化合物製備得到式(3-9)化合物
Figure 108148250-A0305-02-0031-33
式(3-8)化合物與氧化劑在酸性條件下反應製備得到式(3-9)化合物。
The preparation method according to claim 6, further comprising preparing the compound of formula (3-9) by preparing the compound of formula (3-8)
Figure 108148250-A0305-02-0031-33
The compound of formula (3-8) is prepared by reacting the compound of formula (3-8) with an oxidant under acidic conditions to obtain the compound of formula (3-9).
根據請求項9所述的製備方法,其中,所述氧化劑選自NaClO2、重鉻酸吡啶嗡鹽、高錳酸鉀、高碘酸鈉/三氯化釕、 雙氧水/甲酸或二乙酸碘苯/2,2,6,6-四甲基呱啶氧化物;反應使用的溶劑選自水、第三丁醇、二氯甲烷、丙酮、二氧六環和甲苯中的任一種或任幾種任意比例的混合物。 The preparation method according to claim 9, wherein the oxidant is selected from NaClO 2 , pyridinium dichromate, potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid or iodobenzene diacetate /2,2,6,6-tetramethylpyridine oxide; the solvent used in the reaction is selected from any one or several of water, tert-butanol, dichloromethane, acetone, dioxane and toluene Mixtures in any ratio. 根據請求項9所述的製備方法,其中,所述氧化劑選自2-甲基-2-丁烯/NaClO2/NaH2PO4;反應使用的溶劑選自水、第三丁醇、二氯甲烷、丙酮、二氧六環和甲苯中的任一種或任幾種任意比例的混合物。 The preparation method according to claim 9, wherein the oxidant is selected from 2-methyl-2-butene/NaClO 2 /NaH 2 PO 4 ; the solvent used in the reaction is selected from water, tert-butanol, dichloride Any one of methane, acetone, dioxane and toluene or a mixture of any of them in any proportion. 根據請求項9所述的製備方法,其中還包括通過式(3-7)化合物製備得到式(3-8)化合物,
Figure 108148250-A0305-02-0032-34
式(3-7)化合物與氧化劑反應製備得到式(3-8)化合物。
The preparation method according to claim 9, further comprising preparing the compound of formula (3-8) by preparing the compound of formula (3-7),
Figure 108148250-A0305-02-0032-34
The compound of formula (3-7) is prepared by reacting the compound of formula (3-7) with an oxidizing agent to obtain the compound of formula (3-8).
根據請求項12所述的製備方法,其中所述氧化劑選自鄰碘醯苯甲酸、氯鉻酸吡啶鎓鹽、三氧化硫吡啶、戴斯-馬丁氧化劑、瓊斯試劑、二甲基亞碸/草醯氯或TPAP/N-甲基嗎啉;反應使用的溶劑選自乙酸乙酯、二氯甲烷、丙酮和二甲基亞碸中的任一種或任幾種任意比例的混合物。 The preparation method according to claim 12, wherein the oxidizing agent is selected from the group consisting of o-iodobenzoic acid, pyridinium chlorochromate, sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, dimethylsulfite/grass Acyl chloride or TPAP/N-methylmorpholine; the solvent used in the reaction is selected from any one of ethyl acetate, dichloromethane, acetone and dimethylsulfoxide or a mixture of any of them in any proportion. 根據請求項12所述的製備方法,其中還包括通過式(3-6)化合物製備得到式(3-7)化合物
Figure 108148250-A0305-02-0032-36
P選自羥基保護基,反應使用的催化劑選自2,3-二氯-5,6-二氰對苯醌、硝酸鈰銨、三氟甲烷磺酸鈰、Pd/C/H2或四氯化鋯。
The preparation method according to claim 12, further comprising preparing the compound of formula (3-7) by preparing the compound of formula (3-6)
Figure 108148250-A0305-02-0032-36
P is selected from hydroxyl protecting groups, and the catalyst used in the reaction is selected from 2,3-dichloro-5,6-dicyano-p-benzoquinone, cerium ammonium nitrate, cerium trifluoromethanesulfonate, Pd/C/H 2 or tetrachloride zirconium.
根據請求項14所述的製備方法,其中,P為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The preparation method according to claim 14, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl. 根據請求項15所述的製備方法,其中,反應使用的緩衝溶劑選自pH=7的緩衝溶液;反應使用的溶劑選自二氯甲烷、乙腈、氯苯、甲苯、乙二醇二乙醚和硝基甲烷中的任一種或任幾種任意比例的混合物。 The preparation method according to claim 15, wherein the buffer solvent used in the reaction is selected from a buffer solution of pH=7; the solvent used in the reaction is selected from dichloromethane, acetonitrile, chlorobenzene, toluene, ethylene glycol diethyl ether and nitrous Any one or any mixture of any of the base methanes in any proportion. 根據請求項16所述的製備方法,其中,反應使用的緩衝溶劑為pH=7的磷酸鉀緩衝溶液或pH=7的磷酸鈉緩衝溶液。 The preparation method according to claim 16, wherein the buffer solvent used in the reaction is a potassium phosphate buffer solution with pH=7 or a sodium phosphate buffer solution with pH=7. 根據請求項14所述的製備方法,其中還包括通過式(3-4)化合物製備得到式(3-6)化合物
Figure 108148250-A0305-02-0033-37
式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物;所述催化劑選自金屬試劑;反應使用的溶劑選自四氫呋喃,甲苯、二氧六環、乙醚、氯苯和二甲基亞碸中的任一種或任幾種任意比例的混合物。
The preparation method according to claim 14, further comprising preparing the compound of formula (3-6) by preparing the compound of formula (3-4)
Figure 108148250-A0305-02-0033-37
The compound of formula (3-4) is reacted with the compound of formula (3-5) in the presence of a catalyst to prepare the compound of formula (3-6); the catalyst is selected from metal reagents; the solvent used in the reaction is selected from tetrahydrofuran, toluene, dioxygen Any one of hexacyclic ring, diethyl ether, chlorobenzene and dimethyl sulfoxide or a mixture of any of them in any proportion.
一種式(3-6)所示化合物及其立體異構體或其藥學上可接受鹽的製備方法,其特徵在於是通過式(3-4)化合物製備得到,
Figure 108148250-A0305-02-0033-38
P選自羥基保護基;式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物; 所述催化劑選自金屬試劑;反應使用的溶劑選自四氫呋喃,甲苯、二氧六環、乙醚、氯苯和二甲基亞碸中的任一種或任幾種任意比例的混合物。
A preparation method of a compound represented by formula (3-6) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is prepared from a compound of formula (3-4),
Figure 108148250-A0305-02-0033-38
P is selected from hydroxyl protecting groups; the compound of formula (3-4) is reacted with the compound of formula (3-5) in the presence of a catalyst to prepare the compound of formula (3-6); the catalyst is selected from metal reagents; the solvent used in the reaction is selected from From tetrahydrofuran, any one of toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite or a mixture of any of them in any proportion.
根據請求項19所述的製備方法,其中,P為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The preparation method according to claim 19, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl. 根據請求項18或19所述的製備方法,其中,所述催化劑為四氯合銅酸二鋰、碘化亞銅、三氯化鈰、氯化鋰或二氯化鋅。 The preparation method according to claim 18 or 19, wherein the catalyst is dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or zinc dichloride. 根據請求項18-20中任意一項所述的製備方法,其中還包括通過式(3-3)化合物製備得到式(3-4)化合物
Figure 108148250-A0305-02-0034-39
式(3-3)化合物與金屬鎂在催化劑存在下反應製備得到式(3-4)化合物;所述催化劑選自碘、1,2-二氯乙烷或異丙基溴化鎂;反應使用的溶劑選自醚類溶劑。
The preparation method according to any one of claims 18-20, further comprising preparing the compound of formula (3-4) by preparing the compound of formula (3-3)
Figure 108148250-A0305-02-0034-39
The compound of formula (3-3) is reacted with metal magnesium in the presence of a catalyst to prepare the compound of formula (3-4); the catalyst is selected from iodine, 1,2-dichloroethane or isopropylmagnesium bromide; the reaction uses The solvent is selected from ether solvents.
根據請求項22所述的製備方法,其中反應使用的溶劑為四氫呋喃和乙醚中的任一種或任幾種任意比例的混合物。 The preparation method according to claim 22, wherein the solvent used in the reaction is any one of tetrahydrofuran and diethyl ether or a mixture of any of several in any proportion. 根據請求項22所述的製備方法,其中還包括通過式(3-2)化合物製備得到式(3-3)化合物
Figure 108148250-A0305-02-0034-40
式(3-2)化合物與溴化試劑在催化劑存在下反應製備得到式(3-3)化合物;反應使用的溶劑選自乙腈、二氯甲烷、水、四氫呋喃、甲苯、乙醚和乙酸乙酯中的任一種或任幾種任意比例的混合物;所述的催化劑選自膦類化合物;所述的溴化試劑選自四溴化碳、氫溴酸、溴化鈉/硫酸、溴化氰、液溴、三溴 化磷、1-丁基-3-甲基咪唑溴鹽或二溴海因。
The preparation method according to claim 22, further comprising preparing the compound of formula (3-2) to obtain the compound of formula (3-3)
Figure 108148250-A0305-02-0034-40
The compound of formula (3-2) is reacted with a brominating reagent in the presence of a catalyst to prepare the compound of formula (3-3); the solvent used in the reaction is selected from acetonitrile, dichloromethane, water, tetrahydrofuran, toluene, ether and ethyl acetate The mixture of any one or any of several arbitrary proportions; Described catalyst is selected from phosphine compounds; Described bromination reagent is selected from carbon tetrabromide, hydrobromic acid, sodium bromide/sulfuric acid, cyanogen bromide, liquid Bromine, phosphorus tribromide, 1-butyl-3-methylimidazolium bromide or dibromohydantoin.
根據請求項24所述的製備方法,其中所述的催化劑為三苯基膦或三丁基膦。 The preparation method according to claim 24, wherein the catalyst is triphenylphosphine or tributylphosphine. 根據請求項24所述的製備方法,其中還包括通過式(3-1)化合物製備得到式(3-2)化合物
Figure 108148250-A0305-02-0035-41
式(3-1)化合物與羥基保護劑反應製備得到式(3-2)化合物;所述的羥基保護劑選自對甲氧基苄氯、碘甲烷、氯甲基甲醚、第三丁基二甲基氯化矽、第三丁基二苯基氯化矽或苄溴;反應使用的鹼選自氫化鈉、氫化鉀、碳酸鉀、碳酸鈉、碳酸銫、三乙胺、N,N-二異丙基乙胺或4-N,N-二甲基吡啶;反應使用的溶劑選自四氫呋喃、丙酮、乙醚、N-甲基吡咯烷酮、N,N-二甲基甲醯胺和甲苯中的任一種或任幾種任意比例的混合物;反應使用的催化劑選自四丁基碘化銨、碘化鈉、碘化鉀、溴化鈉、溴化鉀或四丁基溴化銨。
The preparation method according to claim 24, further comprising preparing the compound of formula (3-1) to obtain the compound of formula (3-2)
Figure 108148250-A0305-02-0035-41
The compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare a compound of formula (3-2); the hydroxyl protecting agent is selected from p-methoxybenzyl chloride, methyl iodide, chloromethyl methyl ether, tert-butyl Dimethylsilicon chloride, tert-butyldiphenylsilicon chloride or benzyl bromide; the base used in the reaction is selected from sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N- Diisopropylethylamine or 4- N , N -lutidine; the solvent used in the reaction is selected from tetrahydrofuran, acetone, diethyl ether, N-methylpyrrolidone, N,N-dimethylformamide and toluene Any one or several mixtures in any proportion; the catalyst used in the reaction is selected from tetrabutylammonium iodide, sodium iodide, potassium iodide, sodium bromide, potassium bromide or tetrabutylammonium bromide.
一種式(I)所示化合物及其立體異構體或其藥學上可接受鹽的製備方法,其特徵在於
Figure 108148250-A0305-02-0036-42
P選自羥基保護基;a:以式(3-1)化合物為原料,與羥基保護劑反應製備得到式(3-2)化合物;b:以式(3-2)化合物為原料,與溴化試劑反應製備得到式(3-3)化合物;c:以式(3-3)化合物為原料,與金屬鎂反應製備得到式(3-4)化合物;d:以式(3-4)化合物為原料,與式(3-5)化合物製備得到式(3-6)化合物;e:以式(3-6)化合物為原料,與脫保護反應製備得到式(3-7)化合物;f:以式(3-7)化合物為原料,與氧化劑反應製備得到式(3-8)化合物;g:以式(3-8)化合物為原料,與氧化劑反應製備得到式(3-9)化合物;h:以式(3-9)化合物為原料,與吡咯烷在縮合劑存在下,在鹼性條件下反應製備得到式(3-10)化合物;i:以式(3-10)化合物為原料,在鹼性條件下與三氟甲磺酸酐反應製備得到式(3-3)化合物。
A kind of preparation method of compound shown in formula (I) and its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that
Figure 108148250-A0305-02-0036-42
P is selected from a hydroxyl protecting group; a: take the compound of formula (3-1) as a raw material, react with a hydroxyl protecting agent to prepare the compound of formula (3-2); b: take the compound of formula (3-2) as a raw material, react with bromine The compound of formula (3-3) is prepared by reacting a chemical reagent; c: the compound of formula (3-3) is used as a raw material, and the compound of formula (3-4) is prepared by reacting with metal magnesium; d: the compound of formula (3-4) is prepared by As a raw material, the compound of formula (3-5) is prepared with the compound of formula (3-5) to obtain the compound of formula (3-6); e: the compound of formula (3-6) is used as a raw material, and the compound of formula (3-7) is prepared by deprotection reaction; f: Using the compound of formula (3-7) as a raw material, react with an oxidant to prepare a compound of formula (3-8); g: use the compound of formula (3-8) as a raw material, react with an oxidant to prepare a compound of formula (3-9); h: The compound of formula (3-9) is used as the raw material, and the compound of formula (3-10) is prepared by reacting with pyrrolidine in the presence of a condensing agent under basic conditions; i: The compound of formula (3-10) is used as the raw material , and react with trifluoromethanesulfonic anhydride under basic conditions to prepare the compound of formula (3-3).
根據請求項27所述的製備方法,其中,P為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基、苄基。 The preparation method according to claim 27, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl. 根據請求項27所述的製備方法,其中a:反應使用的羥基保護劑選自對甲氧基苄氯,鹼選自氫化鈉,溶劑選自四氫 呋喃,催化劑選自四丁基碘化銨;b:反應使用的溴化試劑選自四溴化碳,溶劑選自乙腈,催化劑選自三苯基膦;c:反應使用的催化劑選自碘,使用的溶劑選自四氫呋喃;d:反應使用的催化劑選自四氯合銅酸二鋰,溶劑選自四氫呋喃;e:反應使用的催化劑選自2,3-二氯-5,6-二氰對苯醌,溶劑選自二氯甲烷,緩衝溶劑選自pH=7的磷酸鉀緩衝溶液;f:反應使用的氧化劑選自鄰碘醯苯甲酸,溶劑選自乙酸乙酯;g:反應使用的氧化體系選自2-甲基-2-丁烯/NaClO2/NaH2PO.2H2O,溶劑選自水和第三丁醇中的任一種或任幾種任意比例的混合物;h:反應使用的縮合試劑選自O-(7-氮雜苯並三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸鹽,鹼選自三乙胺,溶劑選自二氯甲烷;i:反應使用的酸酐為三氟甲磺酸酐,鹼選自2,4,6-三甲基吡啶,進一步在鹼性條件下反應,所述的鹼選自碳酸鉀。 The preparation method according to claim 27, wherein a: the hydroxyl protecting agent used in the reaction is selected from p-methoxybenzyl chloride, the base is selected from sodium hydride, the solvent is selected from tetrahydrofuran, and the catalyst is selected from tetrabutylammonium iodide; b : the brominating reagent used in the reaction is selected from carbon tetrabromide, the solvent is selected from acetonitrile, and the catalyst is selected from triphenylphosphine; c: the catalyst used in the reaction is selected from iodine, and the solvent used is selected from tetrahydrofuran; d: the catalyst used in the reaction is selected from is selected from dilithium tetrachlorocuprate, and the solvent is selected from tetrahydrofuran; e: the catalyst used in the reaction is selected from 2,3-dichloro-5,6-dicyano-p-benzoquinone, the solvent is selected from dichloromethane, and the buffer solvent is selected from From potassium phosphate buffer solution with pH=7; f: the oxidant used in the reaction is selected from o-iodobenzoic acid, and the solvent is selected from ethyl acetate; g: the oxidation system used in the reaction is selected from 2-methyl-2-butene/ NaClO 2 /NaH 2 PO. 2H 2 O, the solvent is selected from any one of water and the third butanol or the mixture of any of them in any ratio; h: the condensation reagent used in the reaction is selected from O-(7-azabenzotriazole-1- base)-bis(dimethylamino)carbonium hexafluorophosphate, the base is selected from triethylamine, and the solvent is selected from dichloromethane; i: the acid anhydride used in the reaction is trifluoromethanesulfonic anhydride, and the base is selected from 2,4 , 6-trimethylpyridine, and further react under basic conditions, and the base is selected from potassium carbonate. 一種製備式(I)所示化合物及其立體異構體或其藥學上可接受鹽的中間體,選自
Figure 108148250-A0305-02-0037-44
P選自羥基保護基;條件是P不為苄基或三氟乙基。
A kind of intermediate for preparing compound shown in formula (I) and its stereoisomer or its pharmaceutically acceptable salt, selected from
Figure 108148250-A0305-02-0037-44
P is selected from hydroxy protecting groups; provided that P is not benzyl or trifluoroethyl.
根據請求項30所述的製備方法,其中,P為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基或第三丁基二苯基矽基。 The preparation method according to claim 30, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.
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