TWI620754B - Method for preparing amino phosphate derivative and preparation method thereof - Google Patents
Method for preparing amino phosphate derivative and preparation method thereof Download PDFInfo
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Abstract
本發明關於一種通式(I)所示具有抗病毒活性的胺基磷酸酯類衍生物製備方法及其中間體和中間體的製備方法。 The present invention relates to a process for preparing an amino phosphate derivative having an antiviral activity represented by the general formula (I), and a process for preparing the intermediate and the intermediate.
Description
本發明關於一類具有抗病毒活性的胺基磷酸酯類衍生物製備方法及其中間體和中間體的製備方法。 The invention relates to a preparation method of a kind of amino phosphate derivative having antiviral activity, a preparation method thereof and an intermediate and an intermediate.
式(I)所示的化合物是一種胺基磷酸酯類衍生物，是替諾福韋(Viread)的一種前藥，可通過直接競爭性地與天然去氧核糖受質相結合而抑制病毒聚合酶，用於治療HIV和HBV感染。 The compound of formula (I) is an amino phosphate derivative which is a prodrug of tenofovir and inhibits viral polymerization by directly competing with natural deoxyribose receptors. Enzyme for the treatment of HIV and HBV infection.
式(I)所示的化合物中R3選自天然或藥學上用胺基酸側鏈；R4選自C1-10烷基。 In the compound of the formula (I), R 3 is selected from a natural or pharmaceutically acceptable amino acid side chain; and R 4 is selected from a C 1 -10 alkyl group.
目前國內外已公開的式(I)所示的化合物的方法主要有以下幾條：
1)CN1443189A公開了以9-(2-(膦醯基甲氧基)丙基]腺嘌呤(PMPA)為起始原料，製備GS-7171。路徑如下：
同時CN1443189A公開了另外一種合成一苯基PMPA(II)的方法：
2)CN101089004A公開了製備路徑中(I)所示的化合物，路徑如下：
WO2013052094公開了製備路徑中15所示的化合物，路徑如下：
目前公開的合成方法中腺嘌呤基團的胺基裸露，中間體以及目標產物的極性大、水溶性好，不利於分離純化。 In the presently disclosed synthetic method, the amine group of the adenine group is exposed, and the intermediate and the target product have high polarity and good water solubility, which is disadvantageous for separation and purification.
本發明的目的在於提供一種新的式(I)所示的胺基磷酸酯類衍生物的製備方法，以及提供用於合成胺基磷酸酯類衍生物的中間體以及中間體的合成方法。 An object of the present invention is to provide a novel process for producing an aminophosphate derivative represented by the formula (I), and a process for synthesizing an intermediate for the synthesis of an aminophosphate derivative and an intermediate.
本發明提供一種式(I)所示的化合物的製備方法：
其中化合物(II)在一定的條件下，發生嘌呤環上胺基脫保護反應；
R1和R2各自獨立選自胺基保護基或氫，條件是R1和R2不同時為氫。 R 1 and R 2 are each independently selected from an amine protecting group or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time.
本發明由化合物(I)製備化合物化合物(II)的一種較佳實施樣態，其中：在0℃~100℃下和溶劑中，使化合物(II)在鹼性試劑、酸性試劑或氫解催化劑下進行胺基脫保護基反應；R1和R2各自獨立選自胺基保護基或氫，條件是R1和R2不同時為氫；R3選自天然或藥學上用胺基酸側鏈；R4選自C1-10烷基；反應中使用的溶劑沒有特別限制，在一定程度上能溶解起始原料並且不抑制反應的溶劑都可以使用；其中所述的溶劑非限制性的選自醇類溶劑、芳烴類溶劑、醚類溶劑、鹵化烷烴類溶劑、酯類溶劑、酮類溶劑、腈類溶劑、醯胺類溶劑、亞碸類溶劑和水中的一種或兩種以上的組合；所述的酸性試劑選自有機酸或無機酸；所述的鹼性試劑選自鹼金屬氫氧化物、鹼土金屬氫氧化物、鹼金屬碳酸鹽、鹼土金屬碳酸鹽和有機胺中的一種或兩種以上的組合；所述的氫解催化劑選自鈀/碳、雷氏鎳(Raney nickel)、鉑/碳或氫氧化鈀/碳；鹼性試劑的用量為化合物(II)的摩爾量的1~10倍；酸性試劑的用量為化合物(II)的摩爾量的1~30倍；氫解催化劑的用量為化合物(II)的摩爾量的0.01~1倍。 A preferred embodiment of the present invention for preparing compound compound (II) from compound (I), wherein compound (II) is used as an alkaline reagent, an acidic reagent or a hydrogenolysis catalyst at 0 ° C to 100 ° C in a solvent. The amine-based deprotection reaction is carried out; R 1 and R 2 are each independently selected from an amine protecting group or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time; and R 3 is selected from the side of the amino acid which is natural or pharmaceutically acceptable. R 4 is selected from C 1 -10 alkyl; the solvent used in the reaction is not particularly limited, and a solvent which can dissolve the starting material to some extent and does not inhibit the reaction can be used; wherein the solvent is not limited One or a combination of two or more selected from the group consisting of an alcohol solvent, an aromatic solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, a nitrile solvent, a guanamine solvent, an anthraquinone solvent, and water The acidic reagent is selected from the group consisting of an organic acid or an inorganic acid; and the alkaline agent is selected from one of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, and an organic amine. Two or more combinations; the hydrogenolysis catalyst From palladium/carbon, Raney nickel, platinum/carbon or palladium hydroxide/carbon; the amount of alkaline reagent is 1 to 10 times the molar amount of compound (II); the amount of acidic reagent is compound (II) The molar amount is 1 to 30 times; the amount of the hydrogenolysis catalyst is 0.01 to 1 times the molar amount of the compound (II).
本發明較佳實施樣態，其中所述的胺基保護基選自取代或未取代的苄基、烷氧基羰基、烷基醯基或芳基醯基。 In a preferred embodiment of the invention, the amine protecting group is selected from a substituted or unsubstituted benzyl, alkoxycarbonyl, alkyl fluorenyl or aryl fluorenyl group.
本發明由化合物(II)製備化合物(I)的一種較佳實施樣態，其中： R1和R2各自獨立選自氫、苄基、對甲氧基苄基、第三丁氧基羰基、苄氧基羰基、乙醯基或苯甲醯基，且R1和R2不同時為氫，較佳地R1和R2選自第三丁氧基羰基； R3是一種天然或藥學上用胺基酸的側鏈，其中的胺基酸，較佳為：甘胺酸、丙胺酸、亮胺酸、異亮胺酸、結胺酸、脯胺酸、***酸、甲硫胺酸、色胺酸、絲胺酸、穀氨醯胺、蘇胺酸、半胱胺酸、組胺酸、天冬醯胺、絡胺酸、天冬胺酸、谷胺酸、萘胺酸或精胺酸，進一步較佳為甘胺酸、丙胺酸、亮胺酸、***酸、天冬醯胺或精胺酸，更優選甘胺酸、丙胺酸或***酸，R3更進一步較佳為丙胺酸的側鏈； R4選自C1-10烷基，較佳為：甲基、乙基、正丙基、烯丙基、異丙基、正丁基、異丁基、第三丁基、正戊基或正壬基，及其各種支鏈異構體等；進一步較佳為：含有1至4個碳原子的低級烷基，非限制性實施例包括甲基、乙基、丙基、烯丙基、異丙基、正丁基、異丁基或第三丁基等； 反應中使用的溶劑選自：乙二醇、甲醇、乙醇、正丙醇、異丙醇、正丁醇、四氫呋喃、***、二氧六環(dioxane)、甲基第三丁基醚、二甲氧乙烷、二乙二醇二甲醚、三甘醇二甲醚、二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、丙酮、丁酮苯、甲苯、氯苯和二甲苯中的一種或兩種以 上的組合，較佳為：甲醇、乙醇、異丙醇、二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、四氫呋喃、2-甲基四氫呋喃、丙酮、***、二氧六環、乙腈、乙酸乙酯、乙酸異丙酯、N,N-二甲基甲醯胺、二甲基亞碸、N-甲基吡咯烷酮和水中的一種或兩種以上的組合，進一步較佳為二氯甲烷、四氫呋喃、二氧六環和水中的一種或兩種以上的組合； 所述的酸性試劑選自：甲酸、乙酸、三氟乙酸、乙二酸、丁二酸、苯甲酸、甲磺酸、乙磺酸、對甲苯磺酸、苯磺酸、磷酸、硫酸、氫氟酸、氫氯酸、氫溴酸和氫碘酸中的一種或兩種以上的組合，較佳為：乙酸、三氟乙酸、氫氯酸和氫溴酸中的一種或兩種以上的組合； 所述的鹼性試劑選自碳酸鉀、碳酸鈉、碳酸銫、碳酸氫鈉、碳酸氫鉀、磷酸氫鈉、磷酸二氫鈉、磷酸鈉、氫氧化鉀、氫氧化鈉、氫氧化鋰、氫氧化鈣、氫氧化鎂、吡啶、4-二甲胺基吡啶、2,6-二甲基吡啶、三乙胺、N,N-二異丙基乙胺、丙胺、甲胺、二甲胺、第三丁胺、苯胺和氨水中的一種或兩種以上的組合，較佳為碳酸鉀、碳酸鈉、碳酸氫鈉、碳酸氫鉀、氫氧化鉀、氫氧化鈉、氫氧化鋰、三乙胺和N,N-二異丙基乙胺中的一種或兩種以上的組合，進一步較佳為：三乙胺、N,N-二異丙基乙胺或其組合； 所述的氫解催化劑選自鈀/碳、雷氏鎳、鉑/碳或氫氧化鈀/碳，較佳為鈀/碳或氫氧化鈀/碳； 鹼性試劑的用量為化合物(II)的摩爾量的1~10倍； 酸性試劑的用量為化合物(II)的摩爾量的1~20倍，較佳為1~10倍； 氫解催化劑的用量為化合物(II)的摩爾量的0.01~1倍； 反應溫度為0℃~60℃，較佳為0℃~50℃，進一步較佳為20℃~50℃。 A preferred embodiment of the present invention for preparing compound (I) from compound (II), wherein: R 1 and R 2 are each independently selected from the group consisting of hydrogen, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, a benzyloxycarbonyl group, an ethyl fluorenyl group or a benzhydryl group, and R 1 and R 2 are not simultaneously hydrogen, preferably R 1 and R 2 are selected from a third butoxycarbonyl group; R 3 is a natural or pharmaceutically acceptable Using a side chain of an amino acid, wherein the amino acid is preferably: glycine, alanine, leucine, isoleucine, leucine, valine, phenylalanine, methionine, Tryptophan, serine, glutamine, sulphate, cysteine, histidine, aspartame, lysine, aspartic acid, glutamic acid, naphthyl acid or spermine The acid is further preferably glycine, alanine, leucine, phenylalanine, aspartame or arginine, more preferably glycine, alanine or phenylalanine, and R 3 is more preferably alanine. a side chain; R 4 is selected from C 1 -10 alkyl, preferably: methyl, ethyl, n-propyl, allyl, isopropyl, n-butyl, isobutyl, tert-butyl, N-pentyl or n-decyl, and various a chain isomer or the like; further preferably: a lower alkyl group having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, propyl, allyl, isopropyl, n-butyl, Isobutyl or tert-butyl, etc.; the solvent used in the reaction is selected from the group consisting of ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dioxane, Methyl third butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triglyme, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, two One or a combination of two or more of methyl chloride, 1,2-dichloroethane, chloroform, trichloroethane, acetone, methyl ethyl ketone, toluene, chlorobenzene and xylene, preferably methanol or ethanol. Isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, diethyl ether, dioxane, acetonitrile, ethyl acetate, isopropyl acetate One or a combination of two or more of ester, N,N-dimethylformamide, dimethylhydrazine, N-methylpyrrolidone and water, further preferably dichloromethane or tetrahydrogen One or a combination of two or more of furan, dioxane and water; the acidic reagent is selected from the group consisting of: formic acid, acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, methanesulfonic acid, ethyl sulfonate One or a combination of two or more of acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid, preferably acetic acid, trifluoroacetic acid, One or a combination of two or more of hydrochloric acid and hydrobromic acid; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate , sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, triethylamine, N, N - a combination of one or more of diisopropylethylamine, propylamine, methylamine, dimethylamine, tert-butylamine, aniline and aqueous ammonia, preferably potassium carbonate, sodium carbonate, sodium hydrogencarbonate, hydrogencarbonate One or a combination of two or more of potassium, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, and N,N-diisopropylethylamine Further preferred is: triethylamine, N,N-diisopropylethylamine or a combination thereof; the hydrogenolysis catalyst is selected from the group consisting of palladium/carbon, Raney nickel, platinum/carbon or palladium hydroxide/carbon, Preferably, it is palladium/carbon or palladium hydroxide/carbon; the amount of the alkaline reagent is 1 to 10 times the molar amount of the compound (II); and the amount of the acidic reagent is 1 to 20 times the molar amount of the compound (II). Preferably, it is 1 to 10 times; the amount of the hydrogenolysis catalyst is 0.01 to 1 times the molar amount of the compound (II); the reaction temperature is 0 ° C to 60 ° C, preferably 0 ° C to 50 ° C, further preferably 20 °C~50°C.
本發明由化合物(II)製備化合物(I)的另一種較佳實施樣態，其中： R1和R2各自獨立選自氫、苄基、對甲氧基苄基、第三丁氧基羰基、苄氧基羰基、乙醯基或苯甲醯基，較佳為第三丁氧基羰基，且R1和R2不同時為氫； R3選自甘胺酸、丙胺酸、亮胺酸、***酸、天冬醯胺或精胺酸的側鏈，較佳為丙胺酸的側鏈； R4選自甲基、乙基、丙基、異丙基、正丁基、異丁基或第三丁基； 反應中使用的溶劑選自甲醇、乙醇、異丙醇、二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、四氫呋喃、2-甲基四氫呋喃、丙酮、***、二氧六環、乙腈、乙酸乙酯、乙酸異丙酯、N,N-二甲基甲醯胺、二甲基亞碸、N-甲基吡咯烷酮和水中的一種或兩種以上的組合，較佳為二氯甲烷、四氫呋喃、二氧六環和水中的一種或兩種以上的組合； 所述的酸性試劑選自：甲酸、乙酸、三氟乙酸、乙二酸、丁二酸、苯甲酸、甲磺酸、乙磺酸、對甲苯磺酸、苯磺酸、磷酸、硫酸、氫氟酸、氫氯酸、氫溴酸和氫碘酸中的一種或兩種以上的組合，較佳為乙酸、三氟乙酸、氫氯酸或氫溴酸； 所述的鹼性試劑選自：碳酸鉀、碳酸鈉、氫氧化鉀、氫氧化鈉、氫氧化鋰、三乙胺和N,N-二異丙基乙胺中的一種或兩種以上的組 合；酸性試劑的用量為化合物(II)的摩爾量的1~20倍，較佳為1~10倍；反應溫度為0℃~60℃，較佳為0℃~50℃，進一步較佳為20℃~50℃。 Another preferred embodiment of the present invention for preparing compound (I) from compound (II) wherein: R 1 and R 2 are each independently selected from the group consisting of hydrogen, benzyl, p-methoxybenzyl, and tert-butoxycarbonyl a benzyloxycarbonyl group, an ethyl fluorenyl group or a benzhydryl group, preferably a third butoxycarbonyl group, and R 1 and R 2 are not simultaneously hydrogen; and R 3 is selected from the group consisting of glycine, alanine, and leucine a side chain of phenylalanine, aspartame or arginine, preferably a side chain of alanine; R 4 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or a third butyl group; the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, One or a combination of two or more of diethyl ether, dioxane, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethylhydrazine, N-methylpyrrolidone and water Preferably, it is a combination of one or more of dichloromethane, tetrahydrofuran, dioxane and water; the acidic reagent is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, and B. One or two of acid, succinic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid More preferably, the combination is acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, and the like. One or a combination of two or more of ethylamine and N,N-diisopropylethylamine; the acidic reagent is used in an amount of from 1 to 20 times, preferably from 1 to 10 times, the mole of the compound (II); The temperature is from 0 ° C to 60 ° C, preferably from 0 ° C to 50 ° C, further preferably from 20 ° C to 50 ° C.
本發明提供一種式(II)所示的化合物的製備方法：
其中是在-78℃~50℃下和溶劑中，使化合物(III)與化合物(IV)進行取代反應；
R1、R2、R3和R4的定義如前所述；X選自氟、氯、溴或碘；反應中使用的溶劑選自芳烴類溶劑、醚類溶劑、鹵化烷烴類溶劑、酯類溶劑、酮類溶劑和腈類溶劑中的一種或兩種以上的組合；所述的取代反應可選擇性地加入鹼性試劑；化合物(IV)的用量為化合物(III)的摩爾量的0.8~7倍。 R 1 , R 2 , R 3 and R 4 are as defined above; X is selected from fluorine, chlorine, bromine or iodine; the solvent used in the reaction is selected from the group consisting of aromatic hydrocarbon solvents, ether solvents, halogenated alkane solvents, esters. One or a combination of two or more of a solvent-like solvent, a ketone solvent, and a nitrile solvent; the substitution reaction may optionally be carried out by adding an alkaline agent; and the compound (IV) is used in an amount of 0.8 based on the molar amount of the compound (III). ~7 times.
本發明由化合物(III)與化合物(IV)製備化合物(II)的一種較佳實施樣態，其中R1、R2、R3和R4的定義如前所述；X選自氯；反應中使用的溶劑選自：二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、四氫呋喃、2-甲基四氫呋喃、1,4-二氧六環、乙腈、丙腈、甲苯和氯苯中的一種或兩種以上的組合；較佳為二氯甲烷、1,2-二氯乙烷、氯仿、四氫呋喃或乙腈，進一步較佳為二氯甲烷；所述的取代反應可選擇性地加入鹼性試劑，所述的鹼性試劑選自碳酸鉀、碳酸鈉、碳酸氫鉀、碳酸氫鈉、氫氧化鉀、氫氧化鈉、氫氧化鋰、磷酸二氫鈉、磷酸氫鈉、三乙胺、丙胺、甲胺、二甲胺、N,N-二異丙基乙胺、4-二甲胺基吡啶、2,6-二甲基吡啶、吡啶、1,8-二氮雜二環十一碳-7-烯、1,8-雙二甲胺基萘、N-甲基嗎啉、嗎啉、哌啶、苯胺和第三丁胺中的一種或兩種以上的組合，較佳為三乙胺、N,N-二異丙基乙胺、4-二甲胺基吡啶、2,6-二甲基吡啶、N-甲基嗎啉、嗎啉、哌啶和苯胺中的一種或兩種以上的組合，進一步較佳為三乙胺或N,N-二異丙基乙胺；化合物(IV)的用量為化合物(III)的摩爾量的0.8~7倍，較佳為1~6倍；反應溫度為-40℃~50℃，較佳為-30℃~40℃，進一步較佳為-30℃~30℃。 A preferred embodiment of the present invention for preparing compound (II) from compound (III) and compound (IV) wherein R 1 , R 2 , R 3 and R 4 are as defined above; X is selected from chlorine; The solvent used is selected from the group consisting of: dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, toluene And one or a combination of two or more of chlorobenzene; preferably dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran or acetonitrile, further preferably dichloromethane; said substitution reaction can be selected An alkaline reagent is selected, which is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, Triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diaza a combination of one or more of dicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N-methylmorpholine, morpholine, piperidine, aniline and tert-butylamine, Triethylamine One or more of N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, N-methylmorpholine, morpholine, piperidine and aniline Further, it is preferably a triethylamine or N,N-diisopropylethylamine; the compound (IV) is used in an amount of 0.8 to 7 times, preferably 1 to 6 times the molar amount of the compound (III); The temperature is -40 ° C to 50 ° C, preferably -30 ° C to 40 ° C, and more preferably -30 ° C to 30 ° C.
本發明由化合物(III)與化合物(IV)反應製備化合物(II)的另一種較佳實施樣態，其中： R1、R2、R3和R4的定義如前所述； X選自氯；所述的取代反應可選擇性地加入鹼性試劑；反應中使用的溶劑選自二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、四氫呋喃、2-甲基四氫呋喃、1,4-二氧六環、乙腈、丙腈、甲苯和氯苯中的一種或兩種以上的組合，較佳為二氯甲烷；所述的鹼性試劑選自碳酸鉀、碳酸鈉、碳酸氫鉀、碳酸氫鈉、氫氧化鉀、氫氧化鈉、氫氧化鋰、磷酸二氫鈉、磷酸氫鈉、三乙胺、丙胺、第三丁胺、N,N-二異丙基乙胺、4-二甲胺基吡啶、2,6-二甲基吡啶、吡啶、1,8-二氮雜二環十一碳-7-烯、1,8-雙二甲胺基萘、N-甲基嗎啉、嗎啉、哌啶和苯胺中的一種或兩種以上的組合，較佳為三乙胺或N,N-二異丙基乙胺；反應溫度為-40℃~50℃；化合物(IV)的用量為化合物(III)的摩爾量的0.8~7倍，較佳為1~6倍。 Another preferred embodiment of the present invention for preparing compound (II) by reacting compound (III) with compound (IV) wherein: R 1 , R 2 , R 3 and R 4 are as defined above; Chlorine; the substitution reaction may optionally be added with an alkaline reagent; the solvent used in the reaction is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran. One or a combination of two or more of 1,4-dioxane, acetonitrile, propionitrile, toluene and chlorobenzene, preferably dichloromethane; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, Potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, triethylamine, propylamine, tert-butylamine, N,N-diisopropylethylamine , 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N- a combination of one or more of methylmorpholine, morpholine, piperidine and aniline, preferably triethylamine or N,N-diisopropylethylamine; reaction temperature is -40 ° C to 50 ° C; The amount of the compound (IV) is the compound (III) The molar amount is 0.8 to 7 times, preferably 1 to 6 times.
本發明提供一種式(II)所示的化合物：
其中，R1、R2、R3和R4的定義如前所述。 Wherein R 1 , R 2 , R 3 and R 4 are as defined above.
本發明提供一種式(III)或者(III-1)所示的化合物的製備方法：
其中，是在0℃~110℃下和溶劑中，使化合物(V)與鹵化試劑進行鹵化反應生成化合物(III)或化合物(III-1)；
R1、R2和X的定義如前所述；反應中使用的溶劑選自鹵化烷烴類溶劑、腈類溶劑和碸類溶劑中的一種或兩種以上的組合；所述的鹵化反應可選擇性加入催化劑，催化劑選自N,N-二甲基甲醯胺、N,N-二甲基苯胺、三乙胺或者吡啶；鹵化試劑的用量為化合物(V)的摩爾量的1~15倍。 R 1 , R 2 and X are as defined above; the solvent used in the reaction is selected from one or a combination of two or more of a halogenated alkane solvent, a nitrile solvent and an anthraquinone solvent; The catalyst is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylaniline, triethylamine or pyridine; the halogenating agent is used in an amount of 1 to 15 times the molar amount of the compound (V). .
本發明由化合物(V)與鹵化試劑進行鹵化反應製備化合物(III)或者化合物(III-1)的一種較佳實施樣態，其中：反應中使用的溶劑選自二氯甲烷、三氯乙烷、乙腈和環丁碸中的一種或兩種以上的組合，較佳為二氯甲烷或者乙腈； 所述的鹵化試劑選自二氯亞碸、草醯氯、三氯化磷、五氯化磷、三氯氧磷、氯化三苯基膦鹽、二溴亞碸、草醯溴、三溴化磷、五溴化磷、三氯氧溴、溴化三苯基膦鹽或1-氯-N,N,2-三甲基丙烯胺，較佳為草醯氯、草醯溴、二氯亞碸、二溴亞碸、五氯化磷或五溴化磷；進一步較佳為草醯氯或者二氯亞碸；製備化合物(III)時，鹵化試劑更佳為草醯氯，溶劑更佳為二氯甲烷；製備化合物(III-1)時，鹵化試劑更佳為二氯亞碸，溶劑更佳為乙腈；所述的鹵化反應可選擇性的加入催化劑，所述的催化劑選自N,N-二甲基甲醯胺；鹵化試劑的用量為化合物(V)的摩爾量的1~10倍，較佳為1~5倍；製備化合物(III)時，反應溫度為0℃~80℃，較佳為0℃~40℃，進一步較佳為0℃~30℃；製備化合物(III-1)時，反應溫度為室溫~85℃，較佳為50℃~85℃，更佳為進一步較佳為70℃~85℃。 A preferred embodiment of the present invention for preparing a compound (III) or a compound (III-1) by halogenation of a compound (V) with a halogenating reagent, wherein the solvent used in the reaction is selected from the group consisting of dichloromethane and trichloroethane. And one or a combination of two or more of acetonitrile and cyclobutyl hydrazine, preferably dichloromethane or acetonitrile; The halogenating agent is selected from the group consisting of dichlorohydrazine, grass chloroform, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine chloride, dibromoarylene, grass bromo, and tribromide. Phosphorus, phosphorus pentabromide, trichlorooxo bromide, triphenylphosphine bromide or 1-chloro-N,N,2-trimethylpropenamine, preferably grass chloro, grass mash, dichloro Azulene, dibromoarylene, phosphorus pentachloride or phosphorus pentabromide; further preferably grassy chlorine or dichlorohydrazine; when compound (III) is prepared, the halogenating agent is more preferably grassy chlorine, and the solvent is better. For the preparation of the compound (III-1), the halogenating agent is more preferably dichlorohydrazine, and the solvent is more preferably acetonitrile; the halogenation reaction may be selectively added to the catalyst, and the catalyst is selected from N, N-dimethylformamide; the halogenating agent is used in an amount of 1 to 10 times, preferably 1 to 5 times the molar amount of the compound (V); when the compound (III) is prepared, the reaction temperature is 0 ° C to 80 ° C. Preferably, it is 0 ° C ~ 40 ° C, further preferably 0 ° C ~ 30 ° C; when the compound (III-1) is prepared, the reaction temperature is room temperature ~ 85 ° C, preferably 50 ° C ~ 85 ° C, more preferably Further preferably, it is 70 ° C to 85 ° C.
本發明提供一種式(III)所示的化合物：
其中，R1、R2和X的定義如前所述。 Wherein R 1 , R 2 and X are as defined above.
本發明提供一種式(V)所示的化合物的製備方法：
其中是在0℃~110℃下和溶劑中，使化合物(VI)與鹼性試劑進行水解反應；
R1和R2的定義如前所述；反應中使用的溶劑沒有特別限制，在一定程度上能溶解起始原料並且不抑制反應的溶劑都可以使用；其中所述的溶劑非限制性的選自醇類溶劑、醚類溶劑、鹵化烷烴類溶劑、酯類溶劑、酮類溶劑、腈類溶劑、醯胺類溶劑、亞碸類溶劑和水中的一種或兩種以上的組合；所述的鹼性試劑選自鹼金屬氫氧化物、鹼土金屬氫氧化物、鹼金屬碳酸鹽、鹼土金屬碳酸鹽和有機胺中的一種或兩種以上的組合；鹼性試劑的用量為化合物(VI)的摩爾量的1~15倍。 R 1 and R 2 are as defined above; the solvent used in the reaction is not particularly limited, and a solvent which can dissolve the starting material to a certain extent and does not inhibit the reaction can be used; wherein the solvent is selected without limitation a combination of one or more of an alcohol solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, a nitrile solvent, a guanamine solvent, an anthraquinone solvent, and water; The agent is selected from the group consisting of one or a combination of two or more of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, and an organic amine; and the amount of the alkaline agent is a mole of the compound (VI). The amount is 1~15 times.
本發明由化合物(VI)製備化合物一種較佳實施樣態：R1和R2的定義如前所述；反應中使用的溶劑選自：乙二醇、甲醇、乙醇、正丙醇、異丙醇、正丁醇、二甲氧乙烷、二乙二醇二甲醚、三甘醇二甲醚、二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、丙酮、丁酮、四氫呋喃、2-甲基四氫呋喃、***、二氧六環、甲基第三丁基醚、乙腈、丙腈、乙酸乙酯、乙酸異丙酯、N,N-二甲基甲醯胺、二甲基亞碸、N-甲基吡咯烷酮和水中的一種或兩種以上的組合，較佳為二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、四氫呋喃、2-甲基四氫呋喃、1,4-二氧六環、乙腈、丙腈、乙酸乙酯、乙酸異丙酯和水中的一種或兩種以上的組合，進一步較佳為二氯甲烷、四氫呋喃、1,4-二氧六環、乙腈、乙酸乙酯、乙酸異丙酯和水中的一種或兩種以上的組合，更佳為乙腈、水或其組合；所述的鹼性試劑選自：碳酸鉀、碳酸鈉、碳酸銫、碳酸氫鈉、碳酸氫鉀、磷酸氫鈉、磷酸二氫鈉、磷酸鈉、氫氧化鉀、氫氧化鈉、氫氧化鋰、氫氧化鈣、氫氧化鎂、三乙胺、丙胺、甲胺、二甲胺、N,N-二異丙基乙胺、第三丁胺、4-二甲胺基吡啶、2,6-二甲基吡啶、吡啶、1,8-二氮雜二環十一碳-7-烯、1,8-雙二甲胺基萘、咪唑、N-甲基嗎啉、嗎啉、哌啶、苯胺、氨水和水合肼中的一種或兩種以上的組合；較佳為碳酸鉀、碳酸鈉、碳酸銫、碳酸氫鈉、碳酸氫鉀、氫氧化鉀、氫氧化鈉、N,N-二異丙基乙胺、三乙胺和氨水中的一種或兩種以上的組合，進一步較佳為碳酸氫鈉、三乙胺和氨水中的一種或兩種以上的組合；鹼性試劑的用量為化合物(VI)的摩爾量的1~10倍，較佳為3~10 倍，進一步較佳為3~6倍；反應溫度為室溫~80℃，較佳為20℃~60℃，進一步較佳為40℃~60℃。 A preferred embodiment of the present invention for preparing a compound from the compound (VI): R 1 and R 2 are as defined above; the solvent used in the reaction is selected from the group consisting of ethylene glycol, methanol, ethanol, n-propanol, and isopropyl alcohol. Alcohol, n-butanol, dimethoxyethane, diethylene glycol dimethyl ether, triglyme, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, dichloromethane 1,2-Dichloroethane, chloroform, trichloroethane, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dioxane, methyl tert-butyl ether, acetonitrile, propionitrile, One or a combination of two or more of ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethylhydrazine, N-methylpyrrolidone and water, preferably dichloromethane, 1 , 2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate and one of water or Further, two or more combinations are further preferably one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, isopropyl acetate and water. More preferably, it is acetonitrile, water or a combination thereof; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, Potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, third butylamine, 4 - dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, imidazole, N- One or a combination of two or more of methylmorpholine, morpholine, piperidine, aniline, aqueous ammonia and hydrazine hydrate; preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or potassium hydroxide One or a combination of two or more of sodium hydroxide, N,N-diisopropylethylamine, triethylamine and aqueous ammonia, further preferably one or two of sodium hydrogencarbonate, triethylamine and aqueous ammonia The above combination; the amount of the alkaline reagent is 1 to 10 times, preferably 3 to 10 times, more preferably 3 to 6 times the molar amount of the compound (VI); the reaction temperature is room temperature to 80 ° C, Good for 20 ° C~ 60 ° C, further preferably 40 ° C ~ 60 ° C.
本發明由化合物(VI)製備化合物(V)的另一種較佳實施樣態，其中：反應中使用的溶劑選自乙腈、水或其組合；所述的鹼性試劑選自碳酸氫鈉、三乙胺和氨水中的一種或兩種以上的組合；鹼性試劑的用量為化合物(VI)的摩爾量的3~6倍；反應的溫度為20℃~60℃。 Another preferred embodiment of the present invention for preparing compound (V) from compound (VI), wherein: the solvent used in the reaction is selected from the group consisting of acetonitrile, water or a combination thereof; and the alkaline agent is selected from the group consisting of sodium hydrogencarbonate, three One or a combination of two or more of ethylamine and ammonia; the amount of the alkaline reagent is 3 to 6 times the molar amount of the compound (VI); and the reaction temperature is 20 to 60 °C.
本發明提供一種式(V)所示的化合物：
其中，R1和R2的定義如前所述。 Wherein R 1 and R 2 are as defined above.
本發明提供一種式(VI)所示的化合物的製備方法：
其中是在0℃~110℃下和溶劑中，使化合物(VII)與胺基保護劑進行反應；
R1和R2的定義如前所述；反應中使用的溶劑選自醇類溶劑、醚類溶劑、鹵化烷烴類溶劑、酮類溶劑、腈類溶劑、酯類溶劑、醯胺類溶劑、亞碸類溶劑和水中的一種或兩種以上的組合；所述的胺基保護反應可選擇性加入催化劑，其中所述的催化劑選自三乙胺、N,N-二異丙基乙胺或4-二甲胺基吡啶；胺基保護劑的用量為化合物(VII)的摩爾量的1~15倍。 R 1 and R 2 are as defined above; the solvent used in the reaction is selected from the group consisting of an alcohol solvent, an ether solvent, a halogenated alkane solvent, a ketone solvent, a nitrile solvent, an ester solvent, a guanamine solvent, and a sub-solvent. a combination of an hydrazine-based solvent and one or more of the two; the amine-based protecting reaction may be optionally added to the catalyst, wherein the catalyst is selected from the group consisting of triethylamine, N,N-diisopropylethylamine or 4 - dimethylaminopyridine; the amine protecting agent is used in an amount of from 1 to 15 times the molar amount of the compound (VII).
本發明由化合物(VII)與胺基保護劑反應製備化合物(VI)的一種較佳實施樣態，其中：R1和R2的定義如前所述；反應中使用的溶劑選自甲醇、乙醇、二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷、四氫呋喃、1,4-二氧六環、乙腈、丙腈、乙酸乙酯、乙酸異丙酯、二甲基甲醯胺、二甲基亞碸、丙酮、丁酮和水中的一種或兩種以上的組合，較佳為二氯甲烷、四氫呋喃和1,4-二氧六環中的一種或兩種以上的組合，進一步較佳為四氫呋喃；胺基保護劑選自二碳酸二第三丁酯、氯甲酸苄酯、乙酸酐、三氟乙酸酐、乙醯氯、苯甲酸酐、苯甲醯氯，苄基溴、苄基氯、對甲氧基苄基溴、對甲氧基苄基氯或三苯甲基氯，較佳為二碳酸二第三丁酯、氯甲酸苄酯、乙酸酐、三氟乙酸酐、乙醯氯、苯甲酸酐或苯甲醯氯，進一步較佳為二碳酸二第三丁酯或氯甲酸苄酯，特別較佳 為二碳酸二第三丁酯；胺基保護劑的用量為化合物(VII)的摩爾量的1~10倍，較佳為1~5倍，進一步較佳為2~5倍；反應溫度為0℃~110℃，較佳為0℃~80℃，進一步較佳為室溫~80℃，特別較佳為50℃~80℃。 A preferred embodiment of the present invention for preparing compound (VI) by reacting compound (VII) with an amine protecting agent, wherein: R 1 and R 2 are as defined above; the solvent used in the reaction is selected from the group consisting of methanol and ethanol. , dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, dimethyl One or a combination of two or more of guanamine, dimethyl hydrazine, acetone, methyl ethyl ketone and water, preferably one or a combination of two or more of dichloromethane, tetrahydrofuran and 1,4-dioxane Further preferred is tetrahydrofuran; the amine protecting agent is selected from the group consisting of ditributin dicarbonate, benzyl chloroformate, acetic anhydride, trifluoroacetic anhydride, ethyl hydrazine chloride, benzoic anhydride, benzamidine chloride, benzyl bromide. , benzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl chloride or trityl chloride, preferably dibutyl butyl carbonate, benzyl chloroformate, acetic anhydride, trifluoroacetic anhydride And acetonitrile, benzoic anhydride or benzamidine chloride, further preferably dibutyl butyl carbonate or benzyl chloroformate, particularly preferably dicarbonic acid The third butyl ester; the amine protecting agent is used in an amount of 1 to 10 times, preferably 1 to 5 times, more preferably 2 to 5 times the molar amount of the compound (VII); and the reaction temperature is 0 ° C to 110 ° C It is preferably 0 ° C to 80 ° C, further preferably room temperature to 80 ° C, and particularly preferably 50 ° C to 80 ° C.
本發明由化合物(VII)與胺基保護劑反應製備化合物(VI)的一種較佳實施樣態，其中：反應中使用的溶劑選自四氫呋喃；胺基保護劑選自二碳酸二第三丁酯；所述的胺基保護反應可選擇性的加入催化劑，所述催化劑選自4-二甲胺基吡啶；胺基保護劑的用量為化合物(VII)的摩爾量的2~5倍；反應溫度為室溫~80℃。 A preferred embodiment of the present invention for preparing compound (VI) by reacting compound (VII) with an amine protecting agent, wherein: the solvent used in the reaction is selected from tetrahydrofuran; and the amine protecting agent is selected from dibutyl butyl dicarbonate. The amine-protecting reaction may optionally be carried out by adding a catalyst selected from the group consisting of 4-dimethylaminopyridine; the amine protecting agent is used in an amount of 2 to 5 times the molar amount of the compound (VII); It is room temperature ~80 °C.
本發明提供一種(VI)所示的化合物，其結構如下所示：
其中，R1和R2各自獨立選自胺基保護基或氫，條件是R1和R2不同時為氫；各自獨立較佳為氫、苄基、對甲氧基苄基、第三丁氧基羰基、苄氧基羰基、乙醯基或苯甲醯基，且R1和R2不同時為氫，較佳為R1和R2選自第三丁氧基羰基。 Wherein R 1 and R 2 are each independently selected from an amine protecting group or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time; each independently preferably hydrogen, benzyl, p-methoxybenzyl, third butyl An oxycarbonyl group, a benzyloxycarbonyl group, an ethyl fluorenyl group or a benzhydryl group, and R 1 and R 2 are not simultaneously hydrogen, and preferably R 1 and R 2 are selected from the group consisting of a third butoxycarbonyl group.
本發明提供一種式(VII)所示的化合物的製備方法，其中包含如下步驟：
(1)化合物(IX)與鹵化試劑進行鹵化反應製得化合物(VIII)；(2)化合物(VIII)與苯酚進行取代反應製得(VII)；
X的定義如前所述。 The definition of X is as described above.
本發明由化合物(IX)製備化合物(VII)的一種較佳實施樣態，其中：X的定義如前所述；步驟(1)中所述的鹵化反應包含下列步驟：溶劑中，在鹵化試劑的作用下，將化合物(IX)進行鹵化反應，製得化合物(VIII)；其中，所述的溶劑選自二氯甲烷、1,2-二氯乙烷、氯仿、乙腈和甲苯中的一種或兩種以上的組合，較佳為二氯甲烷、乙腈和甲苯中的一種或兩種以上的組合；鹵化試劑選自二氯亞碸或草醯氯，較佳為二氯亞碸；鹵化反應可選擇性的加入催化劑，催化劑選自N,N-二甲基甲醯胺；鹵化試劑的用量為化合物(IX)的摩爾量的1~15倍，較佳為1~10倍，進一步較佳為2~6倍；反應的溫度為室溫~110℃，較佳為室溫~85℃，進一步較佳為40℃~85℃；步驟(2)中所述的取代反應包含下列步驟：溶劑中，在鹼性試劑的作用下，將化合物(VIII)進行取代反應，製得化合物(VII)；其中，所述的溶劑選自二氯甲烷、1,2-二氯乙烷、氯仿、三氯乙烷和乙腈中的一種或兩種以上的組合，較佳為二氯甲烷、1,2-二氯乙烷 和乙腈中的一種或兩種以上的組合；所述的鹼性試劑選自三乙胺、二甲胺、N,N-二異丙基乙胺、4-二甲胺基吡啶、2,6-二甲基吡啶、吡啶、N-甲基嗎啉、嗎啉、哌啶、苯胺和第三丁胺中的一種或兩種以上的組合，較佳為三乙胺或N,N-二異丙基乙胺；苯酚的用量為化合物(VIII)的摩爾量的1~8倍，較佳為2~6倍，進一步較佳為2~3倍；鹼性試劑的用量為化合物(VIII)的摩爾量的1~12倍，較佳為4~12倍，進一步較佳為6~12倍；反應溫度為-40℃~70℃，較佳為-30℃~50℃。 A preferred embodiment of the present invention for preparing compound (VII) from compound (IX) wherein: X is as defined above; the halogenation reaction described in step (1) comprises the following steps: in a solvent, in a halogenating reagent The compound (VIII) is obtained by subjecting the compound (IX) to a halogenation reaction, wherein the solvent is selected from one of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile and toluene or A combination of two or more kinds, preferably one or a combination of two or more of dichloromethane, acetonitrile and toluene; the halogenating agent is selected from the group consisting of dichlorohydrazine or chlorinated chlorine, preferably dichlorohydrazine; Optionally, the catalyst is selected from the group consisting of N,N-dimethylformamide; the halogenating agent is used in an amount of from 1 to 15 times, preferably from 1 to 10 times, more preferably from 1 to 10 times the molar amount of the compound (IX). 2 to 6 times; the reaction temperature is room temperature to 110 ° C, preferably room temperature to 85 ° C, further preferably 40 ° C to 85 ° C; the substitution reaction described in the step (2) comprises the following steps: in a solvent a compound (VIII) is subjected to a substitution reaction under the action of an alkaline reagent to obtain a compound (VII); wherein Agent is selected from dichloromethane, 1,2-dichloroethane A chloroform, acetonitrile trichloroethane, and combinations of two or more, preferably dichloromethane, 1,2-dichloroethane And one or a combination of two or more of acetonitrile; the alkaline agent is selected from the group consisting of triethylamine, dimethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6 - one or a combination of two or more of lutidine, pyridine, N-methylmorpholine, morpholine, piperidine, aniline and tert-butylamine, preferably triethylamine or N,N-diiso The amount of the phenol is 1 to 8 times, preferably 2 to 6 times, more preferably 2 to 3 times the molar amount of the compound (VIII); and the amount of the alkaline agent is the compound (VIII). The molar amount is 1 to 12 times, preferably 4 to 12 times, further preferably 6 to 12 times; the reaction temperature is -40 to 70 ° C, preferably -30 to 50 ° C.
本發明由化合物(IX)製備化合物(VII)的另一種較佳實施樣態，其中： 步驟(1)中溶劑選自二氯甲烷、乙腈和甲苯中的一種或兩種以上的組合；鹵化試劑的用量為化合物(IX)的摩爾量的1~10倍；反應的溫度為室溫~80℃； 步驟(2)中所述的溶劑選自二氯甲烷；所述的鹼性試劑選自三乙胺；苯酚的用量為化合物(VIII)的摩爾量的2~3倍；鹼性試劑的用量為化合物(VIII)的摩爾量的6~12倍；反應溫度為-30℃~50℃。 Another preferred embodiment of the invention for preparing compound (VII) from compound (IX) wherein: The solvent in the step (1) is selected from one or a combination of two or more of dichloromethane, acetonitrile and toluene; the halogenating agent is used in an amount of from 1 to 10 times the molar amount of the compound (IX); and the reaction temperature is room temperature. 80 ° C; The solvent described in the step (2) is selected from the group consisting of dichloromethane; the alkaline agent is selected from the group consisting of triethylamine; the amount of the phenol is 2 to 3 times the molar amount of the compound (VIII); and the amount of the alkaline agent is The molar amount of the compound (VIII) is 6 to 12 times; the reaction temperature is -30 ° C to 50 ° C.
本發明提供一種式(I)所示的化合物或者式(III-1)所示的化合物的製備方法，該方法的合成路徑如下：
R1、R2、R3、R4和X的定義如前所述； 該方法為： a.在室溫~85℃下和溶劑中，化合物(IX)與鹵化試劑發生鹵化反應生成化合物(VIII)，溶劑選自二氯甲烷、乙腈或甲苯，較佳為乙腈或甲苯，鹵化試劑選自二氯亞碸或草醯氯，鹵化反應可選擇性地加入催化劑，催化劑選自N,N-二甲基甲醯胺，鹵化試劑的用量為化合物(IX)的1~10倍； b.在-30℃~50℃下和溶劑中，化合物(VIII)與苯酚在鹼性試劑條件下發生取代反應生成化合物(VII)，溶劑選自二氯甲烷、1,2-二氯乙烷、氯仿和乙腈中的一種或兩種以上的組合，鹼性試劑選自三乙胺、N,N-二異丙基乙胺、4-二甲胺基吡啶、2,6-二甲基吡啶中的一種或兩種以上的組合，苯酚的用量為化合物(VIII)的的摩爾量2~3倍，鹼性試劑的用量為化合物(VIII)的摩爾量的6~12倍； c.在室溫~80℃下和溶劑中，化合物(VII)與胺基保護劑反應生成化合物(VI)，溶劑選自甲醇、二氯甲烷、氯仿、1,4-二氧六環、四氫呋喃、乙腈和水中的一種或兩種以上的組合，胺基保護劑選自二碳酸二第三丁酯或氯甲酸苄酯，胺基保護劑的用量為化合物(VII)的摩爾量的1~5倍； d.在20℃~60℃下和溶劑中，化合物(VI)與鹼性試劑發生水解反應生成化合物(V)，溶劑選自二氯甲烷、1,4-二氧六環、乙腈和水中的一種或兩種以上的組合，鹼性試劑選自碳酸氫鈉、碳酸氫鉀、三乙胺和氨水中的一種或兩種以上的組合，鹼性試劑的用量為化合物(VI)的摩爾量的3~6倍； e.在0℃~70℃下和溶劑中，化合物(V)與鹵化試劑發生鹵化反應生成化合物(III)，溶劑選自二氯甲烷或乙腈，鹵化試劑選自草醯氯，鹵化反應可選擇性地加入催化劑，催化劑較佳為N,N-二甲基甲醯胺，鹵化試劑的用量為化合物(V)的摩爾量的1~10倍；或者，在室溫~85℃下和溶劑中，化合物(V)與鹵化試劑發生鹵化反應生成化合物(III-1)，溶劑選自乙腈，鹵化試劑選自二氯亞碸，鹵化試劑的用量為化合物(II)的摩爾量的1~10倍； f.在-40℃~50℃下和溶劑中，化合物(III)與化合物(IV)發生取代反應生成化合物(II)，溶劑選自二氯甲烷、1,2-二氯乙烷、氯仿、乙腈或四氫呋喃，反應可選擇性的加入鹼性試劑，鹼性試劑選自三乙胺、N,N-二異丙基乙胺、4-二甲胺基吡啶和2,6-二甲基吡啶中的一種或兩種以上的組合，化合物(IV)的用量為化合物(III)的摩爾量的1~6倍； g.在0℃~60℃下和溶劑中，化合物(II)在酸性試劑或氫解催化 劑發生胺基脫保護反應生成化合物(I)，溶劑選自二氯甲烷、乙腈、四氫呋喃、二氧六環和水中的一種或兩種以上的組合，酸性試劑選自乙酸、三氟乙酸、氫氯酸或氫溴酸，氫解催化劑選自鈀/碳、雷氏鎳或氫氧化鈀/碳，酸性試劑的用量為化合物(II)的摩爾量的1~10倍，氫解催化劑的用量為化合物(II)的摩爾量的0.01~10倍。 R 1 , R 2 , R 3 , R 4 and X are as defined above; the method is: a. halogenation of compound (IX) with a halogenating reagent to form a compound at room temperature to 85 ° C in a solvent ( VIII), the solvent is selected from the group consisting of dichloromethane, acetonitrile or toluene, preferably acetonitrile or toluene, the halogenating agent is selected from the group consisting of dichlorohydrazine or chloroform, the halogenation reaction can be selectively added to the catalyst, and the catalyst is selected from N, N- Dimethylformamide, the halogenating agent is used in an amount of 1 to 10 times that of the compound (IX); b. The compound (VIII) and the phenol are substituted under an alkaline reagent at -30 ° C to 50 ° C in a solvent. The reaction produces the compound (VII), the solvent is selected from one or a combination of two or more of dichloromethane, 1,2-dichloroethane, chloroform and acetonitrile, and the alkaline agent is selected from the group consisting of triethylamine, N, N-di One or a combination of two or more of isopropylethylamine, 4-dimethylaminopyridine, and 2,6-lutidine, and the amount of the phenol is 2 to 3 times the molar amount of the compound (VIII), and the base is used. The amount of the reagent is 6 to 12 times the molar amount of the compound (VIII); c. The compound (VII) is reacted with an amine protecting agent to form a compound (VI) at room temperature to 80 ° C in a solvent. The solvent is selected from the group consisting of one or a combination of two or more of methanol, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, acetonitrile and water, and the amine-based protecting agent is selected from dibutyl butyl carbonate or The benzyl chloroformate and the amine protecting agent are used in an amount of 1 to 5 times the molar amount of the compound (VII); d. The compound (VI) is hydrolyzed with the alkaline reagent at 20 ° C to 60 ° C in a solvent. Compound (V), the solvent is selected from one or a combination of two or more of dichloromethane, 1,4-dioxane, acetonitrile and water, and the alkaline agent is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine and One or a combination of two or more kinds in the aqueous ammonia, the amount of the alkaline agent is 3 to 6 times the molar amount of the compound (VI); e. the compound (V) and the halogenating agent at 0 ° C to 70 ° C and in a solvent The halogenation reaction occurs to form the compound (III), the solvent is selected from dichloromethane or acetonitrile, the halogenating agent is selected from the group consisting of grass chloroform, the halogenation reaction is selectively added to the catalyst, and the catalyst is preferably N,N-dimethylformamide. The amount of the halogenating agent is 1 to 10 times the molar amount of the compound (V); or, at room temperature to 85 ° C and in the solvent, the compound (V) Halogenation reaction with a halogenating reagent to form compound (III-1), the solvent is selected from acetonitrile, the halogenating agent is selected from the group consisting of dichlorohydrazine, and the halogenating agent is used in an amount of 1 to 10 times the molar amount of the compound (II); f. The compound (III) is substituted with the compound (IV) at -40 ° C to 50 ° C to form the compound (II). The solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile or tetrahydrofuran. The reaction may optionally be carried out by adding an alkaline reagent selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and 2,6-lutidine. Or a combination of two or more kinds, the amount of the compound (IV) is 1 to 6 times the molar amount of the compound (III); g. the compound (II) in an acidic reagent or hydrogenolysis at 0 ° C to 60 ° C and in a solvent The catalyst undergoes amine-based deprotection reaction to form compound (I). The solvent is selected from one or a combination of two or more of dichloromethane, acetonitrile, tetrahydrofuran, dioxane and water. The acidic reagent is selected from the group consisting of acetic acid, trifluoroacetic acid and hydrogen. Chloric acid or hydrobromic acid, the hydrogenolysis catalyst is selected from palladium/carbon, Raney nickel or palladium hydroxide/carbon, and the amount of the acidic reagent is compound (I) The molar amount of I) is 1 to 10 times, and the amount of the hydrogenolysis catalyst is 0.01 to 10 times the molar amount of the compound (II).
本發明由化合物(IX)製備化合物(I)或者化合物(III-1)的一種較佳實施樣態，其中： R1、R2、R3、R4和X的定義如前所述； a.在75℃~85℃下和乙腈中，二氯亞碸與化合物(IX)發生氯代反應，二氯亞碸的用量為化合物(IX)的摩爾量的4~10倍，反應3~4小時； b.在-30℃~50℃下和二氯甲烷中，苯酚與化合物(VIII)在三乙胺作用下反應取代反應，苯酚的用量為化合物(VIII)的摩爾量的2~3倍，三乙胺的用量為化合物(VIII)的摩爾量的6~10倍，反應10~14小時； c.在60℃~72℃下和四氫呋喃中，胺基保護劑與化合物(VII)在4-二甲胺基吡啶作用下發生反應，胺基保護劑選自二碳酸二第三丁酯，二碳酸二第三丁酯的用量為化合物(VII)的的摩爾量的2~4倍，4-二甲胺基吡啶的用量為化合物(VII)的摩爾量的0.2~0.5倍，反應2~4小時； d.在50℃~60℃下和乙腈-水的混合溶劑中，化合物(VI)在三乙胺和氨水作用下發生水解反應，三乙胺的用量為化合物(VI)的的摩爾量的2~5倍，氨水的用量為化合物(VI)的的摩爾量的1~4倍，反應10~14小時； e.在0℃~30℃下和二氯甲烷中，草醯氯與化合物(V)發生氯代反應，草醯氯的用量為化合物(V)的摩爾量的2~5倍，反應1~4小時；或者，在70℃~85℃下和乙腈中，化合物(V)與二氯亞碸發生氯代反應生成(III-1)，二氯亞碸的用量為化合物(V)的摩爾量的2~4倍，反應3~4小時； f.在-30℃~室溫下和二氯甲烷中，化合物(IV)與化合物(III)發生取代反應製備得到(III)，化合物(IV)的用量為化合物(III)的摩爾量的1~6倍； g.在室溫~30℃下和二氯甲烷中，化合物(II)與三氟乙酸作用發生胺基脫保護反應，三氟乙酸的用量為化合物(II)的摩爾量的8~12倍，反應2~3小時。 A preferred embodiment of the present invention for preparing compound (I) or compound (III-1) from compound (IX) wherein: R 1 , R 2 , R 3 , R 4 and X are as defined above; Chlorine reaction of dichlorohydrazine with compound (IX) at 75 ° C ~ 85 ° C and acetonitrile, the amount of dibromide is 4 to 10 times the molar amount of compound (IX), reaction 3 ~ 4 b. Between -30 ° C ~ 50 ° C and dichloromethane, phenol and compound (VIII) in the reaction of triethylamine reaction substitution, the amount of phenol is 2 to 3 times the molar amount of compound (VIII) , the amount of triethylamine used is 6 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 10 to 14 hours; c. at 60 ° C to 72 ° C and in tetrahydrofuran, the amine protecting agent and the compound (VII) are in 4 - The reaction occurs under the action of dimethylaminopyridine, the amine protecting agent is selected from dibutyl butyl dicarbonate, and the dibutyl butyl dicarbonate is used in an amount of 2 to 4 times the molar amount of the compound (VII), 4 - dimethylaminopyridine is used in an amount of 0.2 to 0.5 times the molar amount of the compound (VII), and the reaction is carried out for 2 to 4 hours; d. in a mixed solvent of acetonitrile-water at 50 ° C to 60 ° C, the compound (VI) In the action of triethylamine and ammonia The hydrolysis reaction occurs, the amount of triethylamine is 2 to 5 times the molar amount of the compound (VI), the amount of the ammonia water is 1 to 4 times the molar amount of the compound (VI), and the reaction is 10 to 14 hours; e. Chlorine reacts with compound (V) at 0 °C ~ 30 °C and dichloromethane. The amount of grass chloroform is 2~5 times of the molar amount of compound (V), and the reaction takes 1~4 hours. Or, at 70 ° C ~ 85 ° C and acetonitrile, the compound (V) and chlorinated chlorination reaction to produce (III-1), the amount of dibromide is the molar amount of the compound (V) 2 ~4 times, the reaction is 3~4 hours; f. The compound (IV) is substituted with the compound (III) at -30 ° C ~ room temperature and dichloromethane to prepare (III), the amount of the compound (IV) 1 to 6 times the molar amount of the compound (III); g. The amine group deprotection reaction of the compound (II) with trifluoroacetic acid at room temperature ~ 30 ° C and dichloromethane, the amount of trifluoroacetic acid It is 8 to 12 times the molar amount of the compound (II), and the reaction is carried out for 2 to 3 hours.
本發明提供一種通式(VI)所示的化合物，
R1和R2的定義如前面所述。 The definitions of R 1 and R 2 are as described above.
本發明的詳細說明：除非有相反的陳述，在說明書和申請專利範圍書中使用的術語具有下述含義。 DETAILED DESCRIPTION OF THE INVENTION: Unless otherwise stated, the terms used in the specification and claims are intended to have the following meaning.
本發明所述基團和化合物中所關於的元素碳、氫、氧、硫、氮或鹵素均包括它們的同位素狀態，及本發明所述基團和化合物中所關於的元素：碳、氫、氧、硫或氮任一種進一步被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 referred to in the groups and compounds of the present invention include their isotopic states, and the elements of the groups and compounds of the present invention: carbon, hydrogen, Any of oxygen, sulfur or nitrogen is further replaced by 1 to 5 of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include helium (H) and helium (D, also known as heavy Hydrogen), strontium (T, also known as super-heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
術語“烷基”是指飽和或不飽和的脂肪族烴基團，包括1至20個碳原子的直鏈和支鏈基團。較佳為含有1至10個碳原子的烷基，非限制性實施例包括，甲基、乙基、正丙基、烯丙基、異丙基、正丁基、異丁基、第三丁基、正戊基、正壬基，及其各種支鏈異構體等；更佳為的是含有1至4個碳原子的低級烷基，非限制性實施例包括甲基、乙基、丙基、烯丙基、異丙基、正丁基、異丁基或第三丁基等。 The term "alkyl" refers to a saturated or unsaturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preferred are alkyl groups having from 1 to 10 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, allyl, isopropyl, n-butyl, isobutyl, tert-butyl a group, a n-pentyl group, a n-decyl group, and various branched isomers thereof; more preferably a lower alkyl group having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, and propyl groups. Base, allyl, isopropyl, n-butyl, isobutyl or tert-butyl, and the like.
“取代或未取代的”是指基團可以被取代或不被取代的情形，若在本發明中沒有指出基團可以被取代，則表示該基團為未取代的情形。 "Substituted or unsubstituted" refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.
“取代”是指基團中一個或多個氫原子被其他基團取代的情形，如果所述的基團被氫原子取代，形成的基團與被氫原子取代的基團相同。基團被取代的情形，例如烷基、苄基、烷氧基任一種進一步被0至4個選自H、F、Cl、Br、I、羥基、氰基、C1-4烷基或C1-4烷氧基的取代基所取代，形成的基團包括但不限於氯甲基、三氯甲基、羥基甲基、-CH2OCH3、CH2CH2CN、-OCH2Cl、-OCH2OCH2CH3、4-甲氧基苄基或2,4-二甲氧基苄基。 "Substitution" refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom. In the case where the group is substituted, for example, an alkyl group, a benzyl group or an alkoxy group is further selected from 0 to 4 selected from H, F, Cl, Br, I, hydroxy, cyano, C 1-4 alkyl or C. Substituted by a substituent of 1-4 alkoxy, the group formed includes, but is not limited to, chloromethyl, trichloromethyl, hydroxymethyl, -CH 2 OCH 3 , CH 2 CH 2 CN, -OCH 2 Cl, -OCH 2 OCH 2 CH 3 , 4-methoxybenzyl or 2,4-dimethoxybenzyl.
“醇類溶劑”是指分子結構中含有羥基的溶劑，非限制性實施例包括乙二醇、甲醇、乙醇、正丙醇、異丙醇、正丁醇、正戊醇、仲 戊醇、3-戊醇、異戊醇、特戊醇、正己醇或環己醇等。 "Alcohol solvent" means a solvent having a hydroxyl group in its molecular structure, and non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, and secondary Pentanol, 3-pentanol, isoamyl alcohol, pivalanol, n-hexanol or cyclohexanol.
“醚類溶劑”是指分子結構中醚鍵的溶劑，非限制性實施例包括四氫呋喃、***、二氧六環、甲基第三丁基醚、二甲氧乙烷、二異丙醚、乙基丁基醚、二丁醚、二戊醚、二乙二醇二甲醚和三甘醇二甲醚等。 The "ether solvent" means a solvent of an ether bond in a molecular structure, and non-limiting examples include tetrahydrofuran, diethyl ether, dioxane, methyl tert-butyl ether, dimethoxyethane, diisopropyl ether, and B. Butyl butyl ether, dibutyl ether, dipentyl ether, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether.
“芳烴類溶劑”是指分子結構中含有芳環的溶劑，非限制性實施例包括苯、甲苯、二甲苯或氯苯等。 The "aromatic solvent" means a solvent having an aromatic ring in its molecular structure, and non-limiting examples include benzene, toluene, xylene or chlorobenzene.
“鹵化烷烴類溶劑”是指分子結構中含有鹵素(氟、氯、溴、碘)的烷烴溶劑，非限制性實施例包括二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、五氯己烷、1-氯丁烷和三溴甲烷等。 The "halogenated alkane solvent" means an alkane solvent containing a halogen (fluorine, chlorine, bromine, or iodine) in a molecular structure, and non-limiting examples include dichloromethane, 1,2-dichloroethane, chloroform, tetrachlorination. Carbon, pentachlorohexane, 1-chlorobutane and tribromomethane.
“酯類溶劑”是指分子結構中含有羧酸酯的溶劑，非限制性實施例包括乙酸乙酯、乙酸異丙酯、三乙酸甘油酯、乙醯乙酸乙酯、乙酸異戊酯、乙酸異丙酯、乙酸正丁酯、乙酸正丙酯、乙酸正戊酯、乙酸甲酯、乙酸第二丁酯、甲酸丁酯、甲酸丙酯、甲酸正戊酯或碳酸二乙酯等。 "Ester solvent" means a solvent containing a carboxylic acid ester in a molecular structure, and non-limiting examples include ethyl acetate, isopropyl acetate, triacetin, ethyl acetate, isoamyl acetate, and acetic acid. Propyl ester, n-butyl acetate, n-propyl acetate, n-amyl acetate, methyl acetate, second butyl acetate, butyl formate, propyl formate, n-amyl formate or diethyl carbonate.
“酮類溶劑”是指分子結構中含有酮羰基的溶劑，非限制性實施例包括丙酮、丁酮、苯乙酮、甲基異丁基酮、佛爾酮(Phorone)、異佛爾酮或異亞丙基酮等。 "Ketone solvent" means a solvent containing a ketone carbonyl group in a molecular structure, and non-limiting examples include acetone, methyl ethyl ketone, acetophenone, methyl isobutyl ketone, Phorone, isophorone or Isopropyl ketone and the like.
“腈類溶劑”是指分子結構中含有氰基的溶劑，非限制性實施例包括乙腈、丁腈或苯乙腈等。 The "nitrile solvent" means a solvent containing a cyano group in its molecular structure, and non-limiting examples include acetonitrile, butyronitrile or phenylacetonitrile.
“醯胺類溶劑”是指分子結構中含有醯胺的溶劑，非限制性實施例包括N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N,N-二乙基乙醯胺、六甲基磷醯胺或N-甲基吡咯烷酮等。 "Amidoxime solvent" means a solvent containing a guanamine in a molecular structure, and non-limiting examples include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-di Ethyl acetamide, hexamethylphosphonium or N-methylpyrrolidone.
“亞碸類溶劑”是指分子結構中含有亞硫醯基的溶劑，非限制性 實施例包括二甲基亞碸。 "Alkene-based solvent" means a solvent containing a sulfinyl group in a molecular structure, without limitation Examples include dimethyl hydrazine.
“碸類溶劑”是指分子結構中含有硫醯基的溶劑，非限制性實施例包括環丁碸。 "Hydrazine type solvent" means a solvent containing a thiol group in the molecular structure, and a non-limiting example includes cyclobutyl hydrazine.
“天然或藥學上用胺基酸”：蛋白質分子的基本骨架是胺基酸序列，組成蛋白質的基本胺基酸有20種，這20種基本胺基酸是生物進行蛋白後期修飾的基礎，此外，在這些基本胺基酸的基礎上，生物還會合成羥脯胺酸、羥賴胺酸等衍生出來的胺基酸類型，這些由生物合成的胺基酸統稱為“天然胺基酸”；用人工方法合成的就是“非天然胺基酸”；“藥學上用胺基酸”是指在藥學上可接受的天然或 非天然胺基酸。 "Amino acid for natural or pharmaceutical use": The basic skeleton of a protein molecule is an amino acid sequence, and there are 20 basic amino acids constituting a protein. These 20 basic amino acids are the basis for biological late modification of proteins. On the basis of these basic amino acids, the organism also synthesizes the types of amino acids derived from hydroxyproline, hydroxylysine, etc., which are collectively referred to as "natural amino acids" by biosynthesized amino acids; Artificially synthesized is "unnatural amino acid"; "pharmaceutical amino acid" means pharmaceutically acceptable natural or Non-natural amino acid.
“胺基酸的側鏈”是指胺基酸通式結構中的R取代 基。 "A side chain of an amino acid" means an amino acid formula R substituents in the structure.
“胺基保護基”是指用於胺基保護的基團，該基團適用於保護胺基，使胺基不進行化學反應，但是在分子的其他部分完成所需化學反應之後該基團容易除去。在《有機合成中的保護基》(華東理工大學有機化學教研室譯，榮國斌校，華東理工大學出版社，2004；原書為Protective Groups In Organic Synthesis(third edition),Theodora W.Green and Peter G.M.Wuts著)中胺基的保護一章對胺基保護基做了詳細介紹。本說明書將《有機合成中的保護基》中第494-653頁引用作為本書明書的一部分。 "Amino protecting group" means a group for the protection of an amine group which is suitable for protecting an amine group such that the amine group does not undergo a chemical reaction, but the group is easy after completion of the desired chemical reaction in other parts of the molecule. Remove. In "Protective Bases in Organic Synthesis" (Translated by the Department of Organic Chemistry, East China University of Science and Technology, Rong Guobin School, East China University of Science and Technology Press, 2004; the original book is Protective Groups In Organic Synthesis (third edition), Theodora W. Green and Peter GM The protection of the amine group is described in detail in the chapter on the protection of the amine group in Wuts. This specification refers to pages 494-653 of the "Protective Groups in Organic Synthesis" as part of the book.
“胺基保護基”包括但不限於以下基團：苄基、對甲氧基苄基、三苯甲基、第三丁氧基羰基、苄氧基羰基、9-芴基甲氧羰基、2,2,2-三氯乙氧羰基、乙氧羰基、苄氧基羰基、三氟乙醯基、乙醯基或苯甲醯基。 "Amino protecting group" includes, but is not limited to, the following groups: benzyl, p-methoxybenzyl, trityl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2 , 2,2-trichloroethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, trifluoroethenyl, ethenyl or benzhydryl.
"可選擇性地"意味著隨後所描述的事件或環境可以但不必須發生，包括該事件或環境發生或不發生的場合。例如，“鹵化反應可選擇性地加入催化劑”意味著催化劑可以加入反應但不必須加入反應。 "Optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "halogenation reaction can be selectively added to the catalyst" means that the catalyst can be added to the reaction without necessarily adding to the reaction.
"室溫"是指反應溫度為20℃~30℃。 "Room temperature" means that the reaction temperature is from 20 ° C to 30 ° C.
以下結合附圖及實施例詳細說明本發明的技術方案，但本發明的保護範圍包括但是不限於此。 The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.
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)的單位給出。NMR的測定是用(Bruker Avance III 400和Bruker Avance 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)，內標為四甲基矽烷(TMS)，外標為85%磷酸水溶液。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl hydrazine (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethyl decane (TMS), and the external standard is 85% phosphoric acid aqueous solution.
MS的測定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。 The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的測定使用安捷倫1260DAD高壓液相色譜儀(Zorbax SB-C18 100×4.6mm)。 The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
薄層層析矽膠板使用烟臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(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 tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet. The specification of the tannin sheet used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4. Mm~0.5mm.
柱層析一般使用烟臺黃海矽膠200~300目矽膠為載體。 Column chromatography generally uses Yantai Huanghai Silicone 200-300 mesh silicone as a carrier.
本發明的已知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。 Known starting materials of the invention may be employed or according to methods known in the art. Synthetic, or can be purchased from Titan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology.
實施例中無特殊說明的情況，反應在氮氣氛圍下進行。 In the examples, unless otherwise specified, the reaction was carried out under a nitrogen atmosphere.
實施例中無特殊說明的情況，溶液是指水溶液。 In the examples, unless otherwise stated, the solution means an aqueous solution.
實施例中無特殊說明的情況，反應的溫度為室溫。 In the examples, unless otherwise specified, the temperature of the reaction was room temperature.
室溫為最適宜的溫度，為20℃~30℃。 The room temperature is the optimum temperature, which is 20 ° C ~ 30 ° C.
N為摩爾每升。 N is moles per liter.
BOC，第三丁氧基羰基。 BOC, a third butoxycarbonyl group.
實施例1：(2S)-2-[[[(1R)-2-(6-胺基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]胺基]丙酸異丙酯(化合物1) Example 1: (2S)-2-[[[(1R)-2-(6-Aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)
Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
第一步：6-胺基-9-[(2R)-2-(二苯氧基磷醯基甲氧基)丙基]嘌呤(1C) First step: 6-amino-9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indole (1C)
9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-amine 9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-amine
將[[(1R)-2-(6-胺基嘌呤-9-基)-1-甲基乙氧基]甲基]磷酸(PMPA，Tenofovir)(400g,1.4mol)溶於乙腈(2.5L)中，常溫下滴加二氯亞碸(666g,5.6mol)，升溫至回流反應3小時。將反應液冷却至常溫，濃縮得到化合物6-胺基-9-[(2R)-2-(二氯磷醯基甲氧基)丙基]嘌呤(1B)。 [[(1R)-2-(6-Aminopurine-9-yl)-1-methylethoxy]methyl]phosphoric acid (PMPA, Tenofovir) (400 g, 1.4 mol) was dissolved in acetonitrile (2.5 L) Among them, dichlorohydrazine (666 g, 5.6 mol) was added dropwise at normal temperature, and the mixture was heated to reflux for 3 hours. The reaction solution was cooled to room temperature and concentrated to give the compound 6-amino-9-[(2R)-2-(dichlorophosphonylmethoxy)propyl] hydrazide (1B).
將6-胺基-9-[(2R)-2-(二氯磷醯基甲氧基)丙基]嘌呤(1B)溶於二氯甲烷(2.5L)中，加入苯酚(289.8g,3.08mol)，冷却至-30℃，加入三乙胺調節pH>7，升溫至室溫反應過夜。反應液中加入水(2.0L)，萃取分層，有機相加入無水硫酸鈉乾燥，過濾，濾液減壓濃縮，濃縮殘餘物加入4N的鹽酸溶液(2.0L)，攪拌，然後加入乙酸乙酯(0.5L×2)萃取，水相冷却至0℃，加入氨水，調節pH>7，然後加入二氯甲烷(2.0L×2)萃取，合併二氯甲烷有機相，飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到標題產物6-胺基-9-[(2R)-2-(二苯氧基磷醯基甲氧基)丙基]嘌呤(1C)，土黃色固體(238g，產率38.7%)。 6-Amino-9-[(2R)-2-(dichlorophosphoniomethoxy)propyl]indole (1B) was dissolved in dichloromethane (2.5 L), and phenol (289.8 g, 3.08) was added. Mol), cooled to -30 ° C, added triethylamine to adjust pH > 7, and warmed to room temperature overnight. Water (2.0 L) was added to the reaction mixture, and the mixture was separated and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 0.5L×2) extraction, the aqueous phase is cooled to 0 ° C, ammonia water is added, the pH is adjusted to 7, then extracted with dichloromethane (2.0 L×2), and the organic phase of dichloromethane is combined, washed with saturated sodium chloride solution, anhydrous Drying over sodium sulfate, filtration, and EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (238 g, yield 38.7%).
1H NMR(400MHz,CDCl3)δ 8.33(s,1H),7.87(s,1H),7.34-7.26(m,4H),7.21-7.13(m,4H),7.10-7.05(m,2H),5.86(s,2H),4.35(dd,1H),4.19-4.10(m,2H),4.08-3.98(m,1H),3.90(dd,1H),1.25(d,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.34 - 7.26 (m, 4H), 7.21 - 7.13 (m, 4H), 7.10 - 7.05 (m, 2H) , 5.86 (s, 2H), 4.35 (dd, 1H), 4.19-4.10 (m, 2H), 4.08-3.98 (m, 1H), 3.90 (dd, 1H), 1.25 (d, 3H).
第二步：N-第三丁基氧基-N-[9-[(2R)-2-(二苯氧基磷醯基甲氧 基)丙基]嘌呤-6-基]胺基甲酸第三丁酯(1D) Second step: N-t-butyloxy-N-[9-[(2R)-2-(diphenoxyphosphonium methoxy) Phenyl) hydrazino-6-yl] butyl methacrylate (1D)
Tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-yl]carbamate Tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-yl]carbamate
將6-胺基-9-[(2R)-2-(二苯氧基磷醯基甲氧基)丙基]嘌呤(1C)(238g,0.54mol)溶於四氫呋喃(1L)中，加入4-二甲胺基吡啶(13.2g,0.108mol)，分批次加入二碳酸二第三丁酯(354g,1.62mol)的四氫呋喃(0.5L)溶液，升溫至回流反應2小時。反應液冷却至常溫，加入1N鹽酸溶液(0.5L)，萃取分層，水層用乙酸乙酯(0.3L×2)萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到標題產物N-第三丁基氧基-N-[9-[(2R)-2-(二苯氧基磷醯基甲氧基)丙基]嘌呤-6-基]胺基甲酸第三丁酯(1D)，黑色油狀物，直接用於下一步反應。 6-Amino-9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indole (1C) (238 g, 0.54 mol) was dissolved in tetrahydrofuran (1 L), 4 -Dimethylaminopyridine (13.2 g, 0.108 mol) was added in portions to a solution of dibutyltributate dicarbonate (354 g, 1.62 mol) in tetrahydrofuran (0.5 L), and the mixture was warmed to reflux for 2 hours. The reaction solution was cooled to room temperature, and a 1N aqueous solution of hydrochloric acid (0.5 L) was added, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (0.3 L×2). Product N-tert-butoxy-N-[9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester (1D), a black oil, used directly in the next step.
1H NMR(400MHz,CDCl3)δ 8.83(s,1H),8.17(s,1H),7.37-7.28(m,4H),7.25-7.13(m,6H),4.48-4.39(m,1H),4.28(dd,1H),4.15(dd,1H),4.09-4.00(m,1H),4.01-3.91(m,1H),1.51-1.39(m,18H),1.22(d,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 8.17 (s, 1H), 7.37-7.28 (m, 4H), 7.25-7.13 (m, 6H), 4.48-4.39 (m, 1H) , 4.28 (dd, 1H), 4.15 (dd, 1H), 4.09-4.00 (m, 1H), 4.01-3.91 (m, 1H), 1.51-1.39 (m, 18H), 1.22 (d, 3H).
HPLC純度：Rt=22.04min,97.2%。 HPLC purity: Rt = 22.04 min, 97.2%.
第三步：[(1R)-2-[6-[二(第三丁基氧羰基)胺基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-單磷酸(1E) Third step: [(1R)-2-[6-[bis(t-butyloxycarbonyl)amino]indol-9-yl]-1-methyl-ethoxy]methyl-phenoxy- Monophosphate (1E)
[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid [(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid
將N-第三丁基氧基-N-[9-[(2R)-2-(二苯氧基磷醯基甲氧基)丙基]嘌呤-6-基]胺基甲酸第三丁酯(1D)(345g,0.54mol)溶於乙腈 (0.8L)和水(0.2L，乙腈：水(v/v)=4：1)中，加入三乙胺(273g,2.7mol)，和氨水溶液(36.7g,0.54mol，含量25%)，升溫至50℃反應過夜。反應液冷却至常溫，減壓濃縮，加入飽和碳酸氫鈉溶液(2.0L)，攪拌，用乙酸乙酯(0.5L×2)萃取，水相加入鹽酸溶液調節pH<7，然後用二氯甲烷(0.7L×2)萃取，合併二氯甲烷相，飽和氯化鈉洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到標題產物[(1R)-2-[6-[二(第三丁基氧羰基)胺基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-單磷酸(1E)，暗紅色油狀物(250g，產率82.2%)。 N-tert-butyloxy-N-[9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester (1D) (345 g, 0.54 mol) dissolved in acetonitrile (0.8 L) and water (0.2 L, acetonitrile: water (v/v) = 4:1), triethylamine (273 g, 2.7 mol), and aqueous ammonia solution (36.7 g, 0.54 mol, content 25%) The temperature was raised to 50 ° C and allowed to react overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, a saturated sodium hydrogen carbonate solution (2.0 L), stirred, and extracted with ethyl acetate (0.5 L×2), and the aqueous phase was adjusted to pH <7, and then dichloromethane. (0.7L × 2), extracted, combined with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and then evaporated to give the title product [(1R)-2-[6-[ Alkyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphoric acid (1E), dark red oil (250 g, yield 82.2%).
1H NMR(400MHz,CDCl3)δ 12.53(s,1H),8.81(s,1H),8.59(s,1H),7.29-7.19(m,4H),7.02(m,1H),4.43(d,1H),4.23(dd,1H),3.91(m,2H),3.66-3.61(m,1H),1.42(s,18H),1.09(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 12.53 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 7.29-7.19 (m, 4H), 7.02 (m, 1H), 4.43 (d , 1H), 4.23 (dd, 1H), 3.91 (m, 2H), 3.66-3.61 (m, 1H), 1.42 (s, 18H), 1.09 (d, 3H).
HPLC純度：Rt=12.33min,93.95%。 HPLC purity: Rt = 12.33 min, 93.95%.
31P NMR(162MHz,CDCl3)δ 15.05。 31 P NMR (162 MHz, CDCl 3 ) δ 15.05.
第四步：N-第三丁基氧基-N-[9-[(2R)-2-[[氯(苯氧基)磷醯基]甲氧基]丙基]嘌呤-6-基]胺基甲酸第三丁酯(1F) Fourth step: N-t-butoxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]propyl]indole-6-yl] Tert-butyl carbazate (1F)
tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-yl]carbamate Tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-yl]carbamate
將[(1R)-2-[6-[二(第三丁基氧羰基)胺基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-單磷酸(1E)(10g,17.7mmol)溶於二氯甲烷(100mL)中，加入草醯氯(4.49g,35.4mmol)，滴加N,N-二甲基甲醯胺2滴，攪拌1小時。反應液減壓蒸餾得到標的產物N-第三丁基氧基-N-[9-[(2R)-2-[[氯(苯氧基)磷醯基]甲氧基]丙基]嘌呤-6-基]胺基甲酸第三丁酯(1F)，直接用於下一步反應。 [(1R)-2-[6-[bis(t-butyloxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate ( 1E) (10 g, 17.7 mmol) was dissolved in dichloromethane (100 mL), dichloromethane (4.49 g, 35.4 mmol) was added, and 2 N of N,N-dimethylformamide was added dropwise, and the mixture was stirred for 1 hour. The reaction liquid was distilled under reduced pressure to give the titled product N-t-butyloxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]propyl] hydrazine- 6-yl]tributyl carbamic acid (1F) was used directly in the next reaction.
第五步：(2S)-2-[[[2-[(1R)-6-[二(第三丁氧羰基)胺基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-膦醯基]胺基]丙酸異丙酯(1G) The fifth step: (2S)-2-[[[2-[(1R)-6-[bis(t-butoxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy] Methyl-phenoxy-phosphonium]amino]propionic acid isopropyl ester (1G)
(2S)-2-[[[2-[(1R)-6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate (2S)-2-[[[2-[(1R)-6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
氮氣氛圍下，將N-第三丁基氧基-N-[9-[(2R)-2-[[氯(苯氧基)磷醯基]甲氧基]丙基]嘌呤-6-基]胺基甲酸第三丁酯(1F)(17.7mmol)溶於二氯甲烷(100mL)中，冷却至0℃，滴加L-丙胺酸(3.56g,21.2mmol)的二氯甲烷(100mL)溶液，升溫至常溫反應1小時。反應液中加入飽和氯化鈉溶液(50mL)，萃取分層，有機相無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物用矽膠柱色譜分離提純標題產物(2S)-2-[[[2-[(1R)-6-[二(第三丁氧羰基)胺基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-膦醯基]胺基]丙酸異丙酯(1G)，淺黃色油狀物(5.6g，產率45.9%)。 N-Tertioxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]propyl]pyridin-6-yl under nitrogen atmosphere The third butyl carbazate (1F) (17.7 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 ° C, and then dropwiselylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylyly The solution was heated to normal temperature for 1 hour. Saturated sodium chloride solution (50 mL) was added to the reaction mixture, and the mixture was separated and evaporated, evaporated, evaporated, evaporated. 2-[(1R)-6-[bis(t-butoxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphonyl]amino group Isopropyl propionate (1G), light yellow oil (5.6 g, yield 45.9%).
1H NMR(400MHz,CDCl3)δ 8.84(d,1H),8.28(d,1H),7.33-7.25(m,2H),7.17-7.12(m,3H),5.08-4.92(m,1H),4.47(ddd,1H),4.32-4.22(m,1H),4.08-3.90(m,3H),3.79-3.71(m,1H),3.65-3.49(m,1H),1.44(d,18H),1.30-1.18(m,12H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.84 (d, 1H), 8.28 (d, 1H), 7.33-7.25 (m, 2H), 7.17-7.12 (m, 3H), 5.08-4.92 (m, 1H) , 4.47 (ddd, 1H), 4.32-4.22 (m, 1H), 4.08-3.90 (m, 3H), 3.79-3.71 (m, 1H), 3.65-3.49 (m, 1H), 1.44 (d, 18H) , 1.30-1.18 (m, 12H).
31P NMR(162MHz,CDCl3)δ 23.38,22.13。 31 P NMR (162 MHz, CDCl 3 ) δ 23.38, 22.13.
第六步：(2S)-2-[[[(1R)-2-(6-胺基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]胺基]丙酸異丙酯(化合物1) The sixth step: (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)
Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
將(2S)-2-[[[2-[(1R)-6-[二(第三丁氧羰基)胺基]嘌呤-9-基]-1-甲 基-乙氧基]甲基-苯氧基-膦醯基]胺基]丙酸異丙酯(1G)(5.6g,8.08mmol)溶於二氯甲烷(100mL)中，加入三氟乙酸(9.21g,80.8mmol)，升溫至30℃反應3小時。反應液冷却至0℃，氨水調節pH>7，加入二氯甲烷(50mL)和飽和氯化鈉溶液(50mL)，萃取分層，有機相無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到標題產物(2S)-2-[[[(1R)-2-(6-胺基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]胺基]丙酸異丙酯(化合物1)，黃色油狀物(2.5g,64.9%)。 (2S)-2-[[[2-[(1R)-6-[bis(t-butoxycarbonyl)amino]]-9-yl]-1-yl Isopropyl-ethoxy]methyl-phenoxy-phosphonium]amino]propionic acid isopropyl ester (1G) (5.6 g, 8.08 mmol) was dissolved in dichloromethane (100 mL). 9.21 g, 80.8 mmol), and the mixture was heated to 30 ° C for 3 hours. The reaction solution was cooled to 0 ° C, and the aqueous solution was adjusted to pH <7>, then dichloromethane (50 mL) and saturated sodium chloride (50 mL). (2S)-2-[[[(1R)-2-(6-Aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propyl Isopropyl acrylate (Compound 1), yellow oil (2.5 g, 64.9%).
1H NMR(400MHz,CDCl3)δ 8.33(d,1H),8.02(d,1H),7.34-7.20(m,2H),7.18-7.08(m,2H),7.03-6.98(m,1H),5.91(s,2H),4.96(m,1H),4.40(m,1H),4.22-4.11(m,1H),4.11-3.87(m,3H),3.76-3.44(m,2H),1.34-1.16(m,12H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, 1H), 8.02 (d, 1H), 7.34-7.20 (m, 2H), 7.18-7.08 (m, 2H), 7.03-6.98 (m, 1H) , 5.91 (s, 2H), 4.96 (m, 1H), 4.40 (m, 1H), 4.22-4.11 (m, 1H), 4.11-3.87 (m, 3H), 3.76-3.44 (m, 2H), 1.34 -1.16 (m, 12H).
31P NMR(162MHz,CDCl3)δ 23.70,22.35。 31 P NMR (162 MHz, CDCl 3 ) δ 23.70, 22.35.
實施例2：(2S)-2-[[[(1R)-2-(6-胺基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]胺基]丙酸異丙酯(化合物1) Example 2: (2S)-2-[[[(1R)-2-(6-Aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)
Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
第一步：6-胺基-9-[(2R)-2-[[氯(苯氧基)膦醯基]甲氧基]異丙基]嘌呤(2A) First step: 6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphino)]methoxy]isopropyl]anthracene (2A)
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6 -amine 9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6 -amine
將[(1R)-2-[6-[二(第三丁基氧羰基)胺基]嘌呤-9-基]-1-甲基-乙氧基]甲基-苯氧基-單磷酸(1E)(250g,0.44mol)溶於乙腈(0.8L)中，加入二氯亞碸(104g,0.88mol)，氮氣氛圍下升溫至70℃反應3小時。反應液減壓蒸餾得到標題產物6-胺基-9-[(2R)-2-[[氯(苯氧基)膦醯基]甲氧基]異丙基]嘌呤(2A)，黃色固體，直接用於下一步反應。 [(1R)-2-[6-[bis(t-butyloxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate ( 1E) (250 g, 0.44 mol) was dissolved in acetonitrile (0.8 L), and then dichlorothylene (104 g, 0.88 mol) was added, and the mixture was heated to 70 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure to give the title compound 6-amino-9-[(2.sup..sup..sup..sup. Used directly in the next step.
第二步：(2S)-2-[[[(1R)-2-(6-胺基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]胺基]丙酸異丙酯(化合物1) The second step: (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)
Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
氮氣氛圍下，將6-胺基-9-[(2R)-2-[[氯(苯氧基)膦醯基]甲氧基]異丙基]嘌呤(2A)(40.5g,0.106mol)溶於二氯甲烷(200mL)中，冷却至-20℃，滴加L-丙胺酸(69.5g,0.53mol)的二氯甲烷(300mL)溶液，升溫至常溫反應過夜。反應液中加入水(500mL)，萃取分層，有機相無水硫酸鈉乾燥，過濾，濾液減壓濃縮。殘餘物加入1N鹽酸溶液(500mL)，萃取分層，水相乙酸乙酯(300mL×2)萃取。水層冷却至0℃，用碳酸氫鈉調節pH>7，再加入乙酸乙酯(300mL×1)萃取，飽和氯化鈉洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到標題產物(2S)-2-[[[(1R)-2-(6-胺基嘌呤-9-基)-1-甲基-乙氧基]甲基-苯氧基-磷基]胺基]丙酸異丙酯(化合物1)，淺褐色固體(20g，產率40.0%)。 6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphonium]methoxy]isopropyl]anthracene (2A) (40.5 g, 0.106 mol) The solution was dissolved in dichloromethane (200 mL), cooled to -20 ° C, and a solution of L-alanine (69.5 g, 0.53 mol) in dichloromethane (300 mL) was added dropwise. Water (500 mL) was added to the mixture and the mixture was evaporated. The residue was added to a 1N aqueous solution of hydrochloric acid (500 mL). The aqueous layer was cooled to 0 ° C, EtOAc (EtOAc) (EtOAc) )-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate Propyl ester (Compound 1), light brown solid (20 g, yield 40.0%).
1H NMR(400MHz,CDCl3)δ 8.33(d,1H),8.02(d,1H),7.31(t,1H),7.23(t,1H),7.16-7.09(m,2H),7.02-6.99(m,1H),5.91(s, 2H),5.04-4.89(m,1H),4.47-4.33(m,1H),4.22-4.11(m,1H),4.11-3.87(m,3H),3.76-3.44(m,2H),1.31-1.17(m,12H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, 1H), 8.02 (d, 1H), 7.31 (t, 1H), 7.23 (t, 1H), 7.16-7.09 (m, 2H), 7.02-6.99 (m, 1H), 5.91 (s, 2H), 5.04-4.89 (m, 1H), 4.47-4.33 (m, 1H), 4.22-4.11 (m, 1H), 4.11-3.87 (m, 3H), 3.76 -3.44 (m, 2H), 1.31-1.17 (m, 12H).
HPLC純度：Rt=14.58min,95.36%。 HPLC purity: Rt = 14.85 min, 95.36%.
31P NMR(162MHz,CDCl3)δ 23.70,22.35。 31 P NMR (162 MHz, CDCl 3 ) δ 23.70, 22.35.
MS M/Z(ESI)：476.9(M+1)。 MS M/Z (ESI): 476.9 (M + 1).
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| WO2015040640A2 (en) * | 2013-09-20 | 2015-03-26 | Laurus Labs Private Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
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| WO2002008241A2 (en) * | 2000-07-21 | 2002-01-31 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2004064845A1 (en) * | 2003-01-14 | 2004-08-05 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
| WO2005066189A1 (en) * | 2003-12-30 | 2005-07-21 | Gilead Sciences, Inc. | Phosphonates, monophosphonamidates, bisphosphonamidates for the treatment of viral diseases |
| WO2014032481A1 (en) * | 2012-08-30 | 2014-03-06 | 上海源力生物技术有限公司 | Tenofovir prodrug and pharmaceutical uses thereof |
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