WO2017050032A1 - Ketolide antibiotics intermediate, preparation method therefor, and application thereof - Google Patents

Ketolide antibiotics intermediate, preparation method therefor, and application thereof Download PDF

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WO2017050032A1
WO2017050032A1 PCT/CN2016/093902 CN2016093902W WO2017050032A1 WO 2017050032 A1 WO2017050032 A1 WO 2017050032A1 CN 2016093902 W CN2016093902 W CN 2016093902W WO 2017050032 A1 WO2017050032 A1 WO 2017050032A1
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compound
prepared
dbu
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王鹏
李丕旭
谷向永
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苏州鹏旭医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

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  • the present invention provides a new class of ketolide antibiotic intermediates and a preparation method thereof, taking into account factors such as product yield, purity, and raw material utilization rate.
  • One of the objects of the present invention is to provide a ketone lactone antibiotic intermediate compound.
  • Another object of the present invention is to provide the use of the above ketolide antibiotic intermediate for the preparation of Solithromycin.
  • the compound of the formula I of the present invention can be obtained by the elimination reaction of the compound Ia, and the structural formula of the compound Ia is as follows:
  • Step 1 the compound I4 is reacted at room temperature or low temperature in the presence of an oxidizing agent to prepare the compound I5, wherein the molar ratio of the oxidizing agent to the compound I4 ranges from 1.5:1 to 3:1, and the oxidizing agent is preferably a Sharit reagent;
  • Compound I5 is prepared by reacting compound I5 at 50-50 ° C, DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS in one or more alkaline environments, SelectFluor, NFSI or TBAF fluorine reagent, wherein fluorine
  • the molar ratio of the reagent to the compound I5 ranges from 1:1 to 3:1; in the third step, the compound I6 is reacted in an organic solvent under basic conditions of DBU and NaH to obtain the compound I7.
  • the organic solvent in the third step is preferably acetonitrile or acetone.
  • R 1 includes a phenyl group, a substituted aromatic group or a C1 ⁇ C6 alkyl group.
  • R 1 is preferably a methyl group or a phenyl group, as exemplified by the following scheme, wherein R 1 is a phenyl group and a methyl group, respectively:
  • Another preferred embodiment of the preparation method of the above compound I7 includes the following steps:
  • R 1 includes a phenyl group, a substituted aromatic group or a C1 ⁇ C6 alkyl group.
  • R 1 is preferably a methyl group or a phenyl group, as shown in the following scheme, taking R 1 as a phenyl group as an example:
  • the preparation method of the compound I of the present invention when R in the compound I is H, comprises the step of preparing the compound I7 by the 12-position elimination reaction of the compound I6,
  • Compound I11 is prepared by reacting one or more alkaline environments of DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS in a basic environment of 50--50 ° C, SelectFluor, NFSI or TBAF fluorine reagent, fluorine reagent and compound
  • the molar ratio of I11 ranges from 1:1 to 3:1.
  • R 1 is a phenyl group, a substituted aryl group or a C1 to C6 alkyl group, and more preferably, R 1 is preferably a methyl group or a phenyl group.
  • the molar ratio of the compound I8 to the compound 12 ranges from 1:1 to 1:3.
  • Compound I8 and compound 12 are prepared in an organic solvent under DBU catalysis to obtain compound I9, which may include acetonitrile, NMP, DMF, DMAC, DMSO, DMI, etc. or a suitable mixture of the above, preferably It is acetonitrile.
  • the compound 3' (1 g) was weighed and added to a dry reaction flask, and the mixture was replaced with an inert gas.
  • DCM (8 mL) was added, and the mixture was cooled to below 0 ° C.
  • pyridine (1.02 mL) was added and stirred for 20 min.
  • a solution of BTC (0.7 g) in DCM (2 mL) was added dropwise, and the internal temperature of the dropwise addition process was not higher than 0 ° C, and the mixture was transferred to room temperature for reaction. After completion of the reaction, the reaction was quenched by adding water, liquid separation, extraction, and spin-drying to purify to give the product compound 4', yield 70%.

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Abstract

A ketolide antibiotics intermediate, a preparation method therefor, and application thereof in preparation of solithromycin. The ketolide antibiotics intermediate has a compound structural general formula as shown as follows, and can be prepared by using existing raw materials via several simple steps, the reaction operation is simple and convenient, the utilization rates of macrolides pregnant nucleus raw materials and side chain raw materials are high, and the yield is high. When the ketolide antibiotics intermediate is used for compounding of solithromycin, comprehensively compared with the prior art, the purity and the yield are greatly improved, and good practical value is obtained.

Description

酮内酯类抗生素中间体及其制备方法和应用Ketone lactone antibiotic intermediate, preparation method and application thereof 技术领域Technical field
本发明属于有机药物合成领域，具体涉及大环内酯类之酮内酯抗生素中间体、及其制备方法、和在制备Solithromycin中的应用。The invention belongs to the field of organic drug synthesis, and particularly relates to a ketone lactone antibiotic intermediate of a macrolide, a preparation method thereof and an application thereof in preparing Solithromycin.
背景技术Background technique
目前对大环内酯类抗生素的研究已经进展到第三代，包括酮内酯类抗生素、酰内酯类抗生素等。这些抗生素因与细菌核蛋白体亚基的结合位点有所改变，故能部分克服细菌的耐药性，不仅对原大环内酯类抗生素敏感菌有效，而且还对部分多重耐药菌有活性，目前已成为研究热点。At present, research on macrolide antibiotics has progressed to the third generation, including ketolide antibiotics and acyl lactone antibiotics. These antibiotics have some changes in the binding sites of bacterial ribosome subunits, so they can partially overcome the drug resistance of bacteria, not only for the original macrolide antibiotic-sensitive bacteria, but also for some multi-drug resistant bacteria. Activity has become a research hotspot.
泰利霉素(Telithromycin，HMR3647)是第一个上市的C-11、12位修饰的酮内酯。Solithromycin(CEM-101)是在泰利霉素基础上研发的酮内酯类化合物，该产品由Cempra公司开发，为首个进入临床研究的氟取代酮内酯药物，其除了末端连接的芳杂环与泰利霉素的末端连接不同，在2位还连接一氟原子，可以抑制肽酰基转移酶、影响移位过程、增加其抗菌活性，具有广泛抗菌谱，对耐大环内酯类和酮内酯类抗生素的细菌亦有活性。其抗菌谱广性、耐受性良好，口服给药后其在受试者血浆、组织和细胞内均呈较高浓度。Solithromycin被证实在严重的慢性肝病患者中具有良好的安全性和耐受性。其药代动力学亦显示肝功能下降的病人无需调整剂量。本品治疗社区获得性细菌性肺炎(CABP)的疗效与标准疗法相近，且安全性较高。Telithromycin (HMR3647) is the first C-11, 12-modified ketolide. Solithromycin (CEM-101) is a ketolide compound developed on the basis of telithromycin. This product was developed by Cempra and is the first fluorine-substituted ketolide drug to enter clinical research, except for the terminally attached aromatic heterocyclic ring. Tetramycin has different terminal junctions and is also linked to a fluorine atom at position 2, which inhibits peptide acyltransferase, affects the translocation process, increases its antibacterial activity, has a broad spectrum of antibacterial activity, and is resistant to macrolides and ketolides. Antibiotic-like bacteria are also active. The antibacterial spectrum is broad and well tolerated, and it is highly concentrated in the plasma, tissues and cells of the subject after oral administration. Solithromycin has been shown to be safe and tolerant in patients with severe chronic liver disease. Its pharmacokinetics also show that patients with reduced liver function do not need to adjust the dose. The efficacy of this product in the treatment of community-acquired bacterial pneumonia (CABP) is similar to standard therapy and is safe.
Figure PCTCN2016093902-appb-000001
Figure PCTCN2016093902-appb-000001
现有技术中，Solithromycin的制备方法主要有以下几种：In the prior art, the preparation methods of Solithromycin mainly include the following:
专利US8343936报道了Solithromycin第一代合成方法，其路线以红霉素A为起始原料，侧链的制备在母体结构上进行，原料使用率低。合成路线如下：Patent US8343936 reports the first generation synthesis method of Solithromycin, the route is based on erythromycin A, the preparation of side chains is carried out on the parent structure, and the raw material utilization rate is low. The synthetic route is as follows:
Figure PCTCN2016093902-appb-000002
Figure PCTCN2016093902-appb-000002
专利WO2009055557报道了一种以克拉霉素为起始原料制备Solithromycin的方法，该路线与专利US8343936类似，其侧链的制备同样是在母体结构上进行，降低了原料的实际使用率，且容易导致一些副反应的发生，最终导致最终产品的分离纯化困难。 Patent WO2009055557 reports a method for preparing Solithromycin starting from clarithromycin. The route is similar to the patent US8343936. The preparation of the side chain is also carried out on the parent structure, which reduces the actual use rate of the raw materials and easily leads to The occurrence of some side reactions eventually leads to difficulties in the separation and purification of the final product.
Figure PCTCN2016093902-appb-000003
Figure PCTCN2016093902-appb-000003
专利WO2014145210报道了一种采用汇聚型的路线，把侧链直接合成好之后再与母体结构发生反应，较前述方案有了较大的提高。但与侧链反应得到的中间体需要5步反应才得到最终产品，且需要对侧链上面的氨基进行保护，步骤多，总收率不高，容易导致侧链在经多步合成过程中产生不必要的损失，原子经济性差，成本较高。Patent WO2014145210 reports a convergence type route, which directly synthesizes the side chain and then reacts with the parent structure, which is greatly improved compared with the above scheme. However, the intermediate obtained by the reaction with the side chain requires a 5-step reaction to obtain the final product, and the amino group on the side chain needs to be protected. The number of steps is high, and the total yield is not high, which easily leads to the side chain being produced in the multi-step synthesis process. Unnecessary losses, poor atomic economy and high cost.
Figure PCTCN2016093902-appb-000004
Figure PCTCN2016093902-appb-000004
本发明鉴于上述情况，综合考虑产物收率、纯度、原料利用率等因素，提供一类新的酮内酯抗生素中间体及其制备方法。 In view of the above circumstances, the present invention provides a new class of ketolide antibiotic intermediates and a preparation method thereof, taking into account factors such as product yield, purity, and raw material utilization rate.
发明内容Summary of the invention
本发明目的之一是提供一类酮内酯抗生素中间体化合物。One of the objects of the present invention is to provide a ketone lactone antibiotic intermediate compound.
本发明目的之二是提供上述酮内酯抗生素中间体的制备方法。The second object of the present invention is to provide a process for preparing the above ketone lactone antibiotic intermediate.
本发明另一目的是提供上述酮内酯抗生素中间体在制备Solithromycin上的应用。Another object of the present invention is to provide the use of the above ketolide antibiotic intermediate for the preparation of Solithromycin.
为达到上述目的，本发明采用的技术方案包括：In order to achieve the above object, the technical solution adopted by the present invention includes:
如下通式I结构的酮内酯抗生素中间体及其盐、溶剂合物、多晶型物：A ketolide antibiotic intermediate having the structure of the following formula I and salts, solvates, polymorphs thereof:
Figure PCTCN2016093902-appb-000005
Figure PCTCN2016093902-appb-000005
其中，among them,
R为H、
Figure PCTCN2016093902-appb-000006
或-COOH，R1为苯基、取代的芳香基或C2～C6烷基。R is H,
Figure PCTCN2016093902-appb-000006
Or -COOH, R 1 is phenyl, substituted aryl or C 2 -C 6 alkyl.
本发明通式I的化合物，可通过化合物Ia发生消除反应得到，化合物Ia结构式如下所示：The compound of the formula I of the present invention can be obtained by the elimination reaction of the compound Ia, and the structural formula of the compound Ia is as follows:
Figure PCTCN2016093902-appb-000007
Figure PCTCN2016093902-appb-000007
其中，R1为苯基、取代的芳香基或C2～C6烷基。Wherein R 1 is a phenyl group, a substituted aryl group or a C 2 -C 6 alkyl group.
上述化合物I的制备方法，当R为H时，即上述化合物I为化合物I7时，化合物I4经3-位羟基氧化反应，2-位氟取代反应，11-位、12-位脱保护基反应制备得化合物I7，In the preparation method of the above compound I, when R is H, that is, when the above compound I is the compound I7, the compound I4 is subjected to a 3-position hydroxy oxidation reaction, a 2-position fluorine substitution reaction, and an 11-position, 12-position deprotection reaction. Prepared compound I7,
Figure PCTCN2016093902-appb-000008
Figure PCTCN2016093902-appb-000008
所述氧化反应所用氧化试剂为戴斯-马丁氧化剂、沙瑞特试剂或Corey-Kim氧化试剂，所述氟取代反应所用氟化试剂为N-氟代双苯磺酰胺、SelectFluor或TBAF，所述脱保护反应在碱性条件下水解脱保护基。所述碱性条件包括各种无机碱或各种有机碱，无机碱如碳酸钾、碳酸钠、碳酸氢钠等类似碱，有机碱如三 乙胺、DBU、二甲基吡啶、二异丙基乙胺等类似碱。The oxidizing reagent used in the oxidation reaction is a Dess-Martin periodinane, a Sharit reagent or a Corey-Kim oxidizing reagent, and the fluorinating reagent used in the fluorine substitution reaction is N-fluorobisbenzenesulfonamide, SelectFluor or TBAF. The deprotection reaction hydrolyzes the deprotecting group under basic conditions. The basic conditions include various inorganic bases or various organic bases, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like, and organic bases such as three Ethylamine, DBU, lutidine, diisopropylethylamine and the like.
上述化合物I7的制备方法，优选地，包括如下步骤：The method for preparing the above compound I7 preferably comprises the following steps:
Figure PCTCN2016093902-appb-000009
Figure PCTCN2016093902-appb-000009
步骤一，化合物I4在室温或低温、氧化剂存在条件下反应制备化合物I5，其中，氧化剂与化合物I4的摩尔比范围是1.5:1～3:1，所述氧化剂优选为沙瑞特试剂；步骤二，化合物I5在50～-50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF氟试剂条件下反应制备化合物I6，其中，氟试剂与化合物I5的摩尔比范围是1:1～3:1；步骤三，化合物I6在有机溶剂中，在DBU、NaH碱性条件反应制备得化合物I7。步骤三所述有机溶剂优选为乙腈或丙酮。Step 1, the compound I4 is reacted at room temperature or low temperature in the presence of an oxidizing agent to prepare the compound I5, wherein the molar ratio of the oxidizing agent to the compound I4 ranges from 1.5:1 to 3:1, and the oxidizing agent is preferably a Sharit reagent; Compound I5 is prepared by reacting compound I5 at 50-50 ° C, DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS in one or more alkaline environments, SelectFluor, NFSI or TBAF fluorine reagent, wherein fluorine The molar ratio of the reagent to the compound I5 ranges from 1:1 to 3:1; in the third step, the compound I6 is reacted in an organic solvent under basic conditions of DBU and NaH to obtain the compound I7. The organic solvent in the third step is preferably acetonitrile or acetone.
由化合物I4经化合物I5、化合物I6制备得到化合物I7，其中R1包括苯基、取代的芳香基或C1～C6烷基。更近一步地，R1优选为甲基或苯基，如下述路线所示，分别以R1为苯基和甲基为例：Compound I4 by compound I5, I6 compound was prepared to give compound I7, in which R 1 includes a phenyl group, a substituted aromatic group or a C1 ~ C6 alkyl group. Further, R 1 is preferably a methyl group or a phenyl group, as exemplified by the following scheme, wherein R 1 is a phenyl group and a methyl group, respectively:
Figure PCTCN2016093902-appb-000010
Figure PCTCN2016093902-appb-000010
即R1为苯基时，化合物4合成得到化合物5，化合物5再进一步合成得到化合物6，由化合物6最终制备得到化合物7。That is, when R 1 is a phenyl group, compound 4 is synthesized to obtain compound 5, compound 5 is further synthesized to obtain compound 6, and compound 6 is finally obtained to obtain compound 7.
又如： Another example:
Figure PCTCN2016093902-appb-000011
Figure PCTCN2016093902-appb-000011
即R1为甲基时，化合物4′合成得到化合物5′，化合物5′再进一步合成得到化合物6′，由化合物6′最终制备得到化合物7′。That is, when R 1 is a methyl group, compound 4' is synthesized to give compound 5', compound 5' is further synthesized to obtain compound 6', and compound 6' is finally prepared to obtain compound 7'.
上述化合物I7的制备方法，另一优选方案，包括如下步骤：Another preferred embodiment of the preparation method of the above compound I7 includes the following steps:
Figure PCTCN2016093902-appb-000012
Figure PCTCN2016093902-appb-000012
步骤一，化合物I4在有机溶剂中，在碱性条件反应制备得化合物10，优选DBU碱性条件；步骤二，化合物I10在室温、氧化条件下反应制备化合物I11，其中，氧化剂与化合物I10的摩尔比范围是1:1～3:1，所述氧化剂优选戴斯-马丁氧化剂；步骤三，化合物I11在-50～50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF等氟试剂条件下反应制备化合物I7，氟试剂与化合物I11的摩尔比范围是1:1～3:1。步骤一所述有机溶剂优选为丙酮或乙腈。Step 1, compound I4 is prepared in an organic solvent under basic conditions to obtain compound 10, preferably DBU basic conditions; in step two, compound I10 is reacted at room temperature under oxidizing conditions to prepare compound I11, wherein the oxidizing agent and compound I10 are moles. The ratio is from 1:1 to 3:1, the oxidant is preferably a Dess-Martin oxidant; in step three, the compound I11 is at -50 to 50 ° C, one of DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS or The compound I7 is prepared by reacting a variety of alkaline environments, such as SelectFluor, NFSI or TBAF, with a fluorine reagent and a compound I11 in a molar ratio ranging from 1:1 to 3:1. The organic solvent in the first step is preferably acetone or acetonitrile.
由化合物I4经化合物I10、化合物I11制备得到化合物I7，其中R1包括苯基、取代的芳香基或C1～C6烷基。，更近一步地，R1优选为甲基或苯基，如下述路线所示，以R1为苯基为例： Compound I4 by compound I10, Compound I11 was prepared to give compound I7, in which R 1 includes a phenyl group, a substituted aromatic group or a C1 ~ C6 alkyl group. Further, R 1 is preferably a methyl group or a phenyl group, as shown in the following scheme, taking R 1 as a phenyl group as an example:
Figure PCTCN2016093902-appb-000013
Figure PCTCN2016093902-appb-000013
即R1为苯基时，化合物4合成得到化合物10，化合物10再进一步合成得到化合物11，由化合物11最终制备得到化合物7。That is, when R 1 is a phenyl group, compound 4 is synthesized to obtain compound 10, compound 10 is further synthesized to obtain compound 11, and compound 11 is finally obtained to obtain compound 7.
上述化合物I7的制备方法，还可优选地，包括如下步骤：The method for preparing the above compound I7 may also preferably include the following steps:
Figure PCTCN2016093902-appb-000014
Figure PCTCN2016093902-appb-000014
步骤一，化合物I4在氧化条件下反应制备化合物I5，其中，沙瑞特试剂与化合物I4的摩尔比范围2:1～5:1，反应条件优选室温和沙瑞特试剂氧化条件；步骤二，化合物I5在有机溶剂中，在DBU、NaH碱性条件反应制备得化合物I11；步骤三，化合物I11在-50～50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF氟试剂条件下反应制备化合物I7，氟试剂与化合物I11的摩尔比范围是1:1～3:1。步骤二所述有机溶剂优选为乙腈或丙酮。Step 1, the compound I4 is reacted under oxidizing conditions to prepare the compound I5, wherein the molar ratio of the Sharit reagent to the compound I4 ranges from 2:1 to 5:1, and the reaction conditions are preferably room temperature and the siridine reagent oxidation condition; step two, the compound I5 is prepared in an organic solvent by reacting DBU and NaH under basic conditions to obtain a compound I11; in step 3, the compound I11 is at -50 to 50 ° C, one or more of DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS. The compound I7 is prepared by reacting in an alkaline environment under the conditions of a SelectFluor, NFSI or TBAF fluorine reagent. The molar ratio of the fluorine reagent to the compound I11 ranges from 1:1 to 3:1. The organic solvent in the second step is preferably acetonitrile or acetone.
由化合物I4经化合物I5、化合物I11制备得到化合物I7，其中R1包括苯基、取代的芳香基或C1～C6烷基。，更近一步地，R1优选为甲基或苯基，如下述路线所示，以R1为苯基为例： Compound I4 by compound I5, I11 compound was prepared to give compound I7, in which R 1 includes a phenyl group, a substituted aromatic group or a C1 ~ C6 alkyl group. Further, R 1 is preferably a methyl group or a phenyl group, as shown in the following scheme, taking R 1 as a phenyl group as an example:
Figure PCTCN2016093902-appb-000015
Figure PCTCN2016093902-appb-000015
即R1为苯基时，化合物4合成得到化合物5，化合物5再进一步合成得到化合物11，由化合物11最终制备得到化合物7。That is, when R 1 is a phenyl group, compound 4 is synthesized to obtain compound 5, compound 5 is further synthesized to obtain compound 11, and compound 11 is finally obtained to obtain compound 7.
应当说明的是，本发明化合物I的制备方法，当化合物I中R为H时，包括化合物I6经12-位消除反应制备得化合物I7的步骤，It should be noted that the preparation method of the compound I of the present invention, when R in the compound I is H, comprises the step of preparing the compound I7 by the 12-position elimination reaction of the compound I6,
Figure PCTCN2016093902-appb-000016
Figure PCTCN2016093902-appb-000016
其中，化合物6在有机溶剂中，DBU、NaH碱性条件反应制备得化合物7，所述Wherein compound 6 is reacted in an organic solvent with DBU and NaH under basic conditions to obtain compound 7,
R1包括苯基、取代的芳香基或C1～C6烷基，更近一步地，R1优选为甲基或苯基。应当说明的是，本发明化合物I的制备方法，当化合物I中，R为H时，包括化合物I11经2-位氟取代反应制备得化合物I7的步骤，R 1 includes a phenyl group, a substituted aryl group or a C1 to C6 alkyl group, and more recently, R 1 is preferably a methyl group or a phenyl group. It should be noted that, in the preparation method of the compound I of the present invention, when R is H in the compound I, the step of preparing the compound I7 by the 2-position fluorine substitution reaction of the compound I11,
Figure PCTCN2016093902-appb-000017
Figure PCTCN2016093902-appb-000017
化合物I11在50～-50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF氟试剂条件下反应制备化合物I7，氟试剂与化合物I11的摩尔比范围是1:1～3:1,所述Compound I11 is prepared by reacting one or more alkaline environments of DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS in a basic environment of 50--50 ° C, SelectFluor, NFSI or TBAF fluorine reagent, fluorine reagent and compound The molar ratio of I11 ranges from 1:1 to 3:1.
R1包括苯基、取代的芳香基或C1～C6烷基。，更近一步地，R1优选为甲基或苯基。 R 1 includes a phenyl group, a substituted aryl group or a C1-C6 alkyl group. Further, R 1 is preferably a methyl group or a phenyl group.
本发明化合物I的制备方法，化合物I的R为
Figure PCTCN2016093902-appb-000018
时的化合物I8，由化合物I7制备而得：For the preparation of the compound I of the present invention, the R of the compound I is
Figure PCTCN2016093902-appb-000018
Compound I8 when prepared from compound I7:
Figure PCTCN2016093902-appb-000019
Figure PCTCN2016093902-appb-000019
其中，化合物I7在室温及DBU碱性条件下反应制备化合物8，所述R1包括苯基、取代的芳香基或C1～C6烷基。更近一步地，R1优选为甲基或苯基。Wherein the compound I7 prepared by reacting a compound of DBU at room temperature under basic conditions to 8, of R 1 include phenyl, substituted aromatic group or a C1 ~ C6 alkyl group. Further, R 1 is preferably a methyl group or a phenyl group.
本发明上述化合物I8，可作为一种医药中间体用于Solithromycin的制备。本发明提供了一种以化合物化合物I8为原料制备Solithromycin的方法，反应路线如下：The above compound I8 of the present invention can be used as a pharmaceutical intermediate for the preparation of Solithromycin. The invention provides a method for preparing Solithromycin by using compound compound I8 as a raw material, and the reaction route is as follows:
化合物I8与化合物12取代成环反应后制备化合物I9，化合物I9水解制备得化合物Solithromycin，所述Compound I8 is compounded with compound 12 to form a compound I9, and compound I9 is hydrolyzed to obtain a compound Solithromycin.
R1为苯基、取代的芳香基或C1～C6烷基，更近一步地，R1优选为甲基或苯基。R 1 is a phenyl group, a substituted aryl group or a C1 to C6 alkyl group, and more preferably, R 1 is preferably a methyl group or a phenyl group.
优选地，所述化合物I8与化合物12的摩尔比范围是1:1～1:3。所述化合物I8与化合物12在有机溶剂中、DBU催化条件下制备得到化合物I9，所述有机溶剂可包括乙腈、NMP、DMF、DMAC、DMSO、DMI等或上述合适的混合物，所述有机溶剂优选为乙腈。Preferably, the molar ratio of the compound I8 to the compound 12 ranges from 1:1 to 1:3. Compound I8 and compound 12 are prepared in an organic solvent under DBU catalysis to obtain compound I9, which may include acetonitrile, NMP, DMF, DMAC, DMSO, DMI, etc. or a suitable mixture of the above, preferably It is acetonitrile.
在上述由化合物I8制备Solithromycin的方法中，优选地，化合物I9在NH3·MeOH条件下水解制备得到Solithromycin。In the above process for preparing Solithromycin from the compound I8, preferably, the compound I9 is hydrolyzed under NH 3 · MeOH to obtain Solithromycin.
本发明提供一类酮内酯抗生素中间体及其制备方法和在制备Solithromycin上的应用。该类酮内酯抗生素中间体可以用现有的原料经简单的几步反应制得，反应操作简便，大环内酯类母核原料及侧链原料利用率高，收率较高。类酮内酯抗生素中间体用于Solithromycin的合成时纯度和收率综合比较现有技术有很大的进步，有很好的实用价值。The invention provides a ketone lactone antibiotic intermediate, a preparation method thereof and application thereof in preparing Solithromycin. The ketolide antibiotic intermediate can be obtained by a simple reaction in a few steps using the existing raw materials, and the reaction operation is simple, and the macrolide lactone raw material and the side chain raw material have high utilization rate and high yield. The purity and yield of the ketolide antibiotic intermediate used in the synthesis of Solithromycin have been greatly improved compared with the prior art, and have good practical value.
具体实施方式detailed description
以下用实施例进一步说明本发明，但所述实施例不构成对本发明范围的限制。The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
实施例1，化合物2的制备。 Example 1, Preparation of Compound 2.
Figure PCTCN2016093902-appb-000021
Figure PCTCN2016093902-appb-000021
称取化合物1(270g)加入反应瓶中，量取EtOH(1.32L)和H2O(3.24L)加入反应瓶中，室温搅拌20min。之后滴加入1N·HCl(0.65L)。HCl滴加完毕后，室温反应。待原料反应完全，开始加入2N·NaOH溶液调节pH至10-11，析出大量固体。接着开始室温搅拌反应计时2h。反应液抽滤，滤饼用800mL冷却水洗涤。滤饼在50℃鼓风烘箱烘料，得到白色固体。收率82％。Compound 1 (270 g) was weighed into a reaction flask, and EtOH (1.32 L) and H 2 O (3.24 L) were weighed and added to the reaction flask, and stirred at room temperature for 20 min. Then, 1N·HCl (0.65 L) was added dropwise. After the dropwise addition of HCl, the reaction was carried out at room temperature. After the reaction of the starting material was completed, the addition of 2N·NaOH solution was started to adjust the pH to 10-11, and a large amount of solid was precipitated. Then, the reaction was stirred at room temperature for 2 h. The reaction solution was suction filtered, and the filter cake was washed with water (800 mL). The filter cake was baked in a forced air oven at 50 ° C to give a white solid. The yield was 82%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ5.18(dd,J＝11.1,2.5Hz,1H),4.39(d,J＝7.3Hz,1H),3.92(s,1H),3.86(d,J＝1.5Hz,2H),3.69(d,J＝1.5Hz,1H),3.59–3.48(m,3H),3.31–3.19(m,2H),3.07–2.91(m,4H)。 1 H NMR (400MHz, CDCl3) δ5.18 (dd, J = 11.1,2.5Hz, 1H), 4.39 (d, J = 7.3Hz, 1H), 3.92 (s, 1H), 3.86 (d, J = 1.5 Hz, 2H), 3.69 (d, J = 1.5 Hz, 1H), 3.59 - 3.48 (m, 3H), 3.31 - 3.19 (m, 2H), 3.07 - 2.91 (m, 4H).
实施例2，化合物3的制备。Example 2, Preparation of Compound 3.
Figure PCTCN2016093902-appb-000022
Figure PCTCN2016093902-appb-000022
称取化合物2(150g)加入反应瓶中，量取DCM(525mL)加入反应瓶，室温搅拌使其全溶。称取苯甲酸酐(86.3g)，三乙胺(38.6g)加入反应瓶，N2保护。室温搅拌反应。待反应完全。加入饱和NaHCO3溶液，搅拌30min，淬灭反应。反应液中加入DCM和水，分液，收集有机相。水相用DCM萃取，合并有机相。有机相用水洗涤，收集有机相，有机相用无水Na2SO4干燥。有机相减压旋干，得到粗品。粗品用EA和正己烷重结晶，得产品化合物3，收率97％。Compound 2 (150 g) was weighed into a reaction flask, and DCM (525 mL) was weighed and added to the reaction flask, and the mixture was stirred at room temperature to be completely dissolved. Benzoic anhydride (86.3 g) and triethylamine (38.6 g) were weighed into a reaction flask and protected with N 2 . The reaction was stirred at room temperature. Wait until the reaction is complete. A saturated NaHCO 3 solution was added and stirred for 30 min to quench the reaction. DCM and water were added to the reaction mixture, and the organic phase was collected. The aqueous phase was extracted with DCM and the organic phases were combined. The organic phase was washed with water, organic phase was collected, the organic phase was dried over anhydrous Na 2 SO 4. The organic phase was dried under reduced pressure to give a crude material. The crude product was recrystallized from EA and n-hexane to afford product product 3, yield 97%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.10–8.03(m,2H),7.61–7.53(m,1H),7.44(dd,J＝10.6,4.7Hz,2H),5.12(dd,J＝11.1,2.4Hz,1H),5.04(dd,J＝10.5,7.6Hz,1H),4.75(d,J＝7.6Hz,1H),3.91(s,1H),3.78–3.72(m,2H),3.56(s,1H),3.49–3.41(m,1H),3.22(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ8.10-8.03 (m, 2H), 7.61-7.53 (m, 1H), 7.44 (dd, J = 10.6,4.7Hz, 2H), 5.12 (dd, J = 11.1 , 2.4 Hz, 1H), 5.04 (dd, J = 10.5, 7.6 Hz, 1H), 4.75 (d, J = 7.6 Hz, 1H), 3.91 (s, 1H), 3.78 - 3.72 (m, 2H), 3.56 (s, 1H), 3.49 - 3.41 (m, 1H), 3.22 (s, 1H).
实施例3，化合物4的制备。Example 3, Preparation of Compound 4.
Figure PCTCN2016093902-appb-000023
Figure PCTCN2016093902-appb-000023
称取化合物3(78g)加入反应瓶中，量取DCM(624mL)加入反应瓶，室温搅拌使其全溶。冰盐浴降温，加入吡啶(71.2g)，继续降温搅拌反应。滴加BTC(50g)的DCM(156mL)溶液，滴加完毕，转至室温下反应，TLC检测反应至原料反应完全。体系降温，加入饱和食盐水淬灭反应。分液，水相用DCM萃取，合并有机 相。有机相用Brine洗涤，收集有机相，用无水Na2SO4干燥，减压旋干得到化合物4粗品。向粗品用乙酸异丙酯和正己烷纯化，得产品化合物4，收率77％。Compound 3 (78 g) was weighed into a reaction flask, and DCM (624 mL) was weighed and added to the reaction flask, and the mixture was stirred at room temperature to be completely dissolved. The ice salt bath was cooled, pyridine (71.2 g) was added, and the reaction was continued while cooling. A solution of BTC (50 g) in DCM (156 mL) was added dropwise, and the mixture was transferred to room temperature. The reaction was carried out by TLC until the reaction was completed. The system was cooled, and the reaction was quenched by the addition of saturated brine. The layers were separated and the aqueous phase was extracted with DCM. The organic phase was washed with Brine, organic phase was collected, dried over anhydrous Na 2 SO 4, rotary evaporation under reduced pressure to give crude compound 4. Purification with crude isopropyl acetate and n-hexane afforded product product 4 in yield 77%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.10–8.03(m,2H),7.56(dd,J＝10.5,4.3Hz,1H),7.44(t,J＝7.7Hz,2H),5.10–4.99(m,2H),4.75(d,J＝7.6Hz,1H),4.69(s,1H),3.73(d,J＝2.6Hz,1H),3.62–3.51(m,1H),3.45(dd,J＝10.5,5.9Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 - 8.03 (m, 2H), 7.56 (dd, J = 10.5, 4.3 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 5.10 - 4.99 ( m, 2H), 4.75 (d, J = 7.6 Hz, 1H), 4.69 (s, 1H), 3.73 (d, J = 2.6 Hz, 1H), 3.62 - 3.51 (m, 1H), 3.45 (dd, J =10.5, 5.9 Hz, 1H).
实施例4，化合物10的制备。Example 4, Preparation of Compound 10.
Figure PCTCN2016093902-appb-000024
Figure PCTCN2016093902-appb-000024
称取化合物4(1g)加入反应瓶中，加入丙酮(15mL)，搅拌溶解，加入DBU(0.53g)，加热回流反应。反应结束，冷却降温，旋干过柱，得产品，收率60％。Compound 4 (1 g) was weighed into a reaction flask, acetone (15 mL) was added thereto, and the mixture was stirred and dissolved. DBU (0.53 g) was added thereto, and the mixture was heated to reflux. The reaction was completed, cooled and cooled, and the column was spin-dried to obtain a product in a yield of 60%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.14–8.06(m,2H),7.57–7.49(m,1H),7.44(dd,J＝10.4,4.6Hz,2H),6.34(d,J＝1.2Hz,1H),5.05–4.96(m,1H),4.94–4.84(m,2H),3.89(d,J＝3.0Hz,1H),3.60(d,J＝10.2Hz,2H),3.12(s,4H)。 1 H NMR (400MHz, CDCl3) δ8.14-8.06 (m, 2H), 7.57-7.49 (m, 1H), 7.44 (dd, J = 10.4,4.6Hz, 2H), 6.34 (d, J = 1.2Hz , 1H), 5.05–4.96 (m, 1H), 4.94–4.84 (m, 2H), 3.89 (d, J=3.0 Hz, 1H), 3.60 (d, J = 10.2 Hz, 2H), 3.12 (s, 4H).
实施例5，化合物11的制备。Example 5, Preparation of Compound 11.
方案1：plan 1:
Figure PCTCN2016093902-appb-000025
Figure PCTCN2016093902-appb-000025
称取化合物5(6.24g)加入反应瓶中，加入MeCN(62mL)搅拌溶解。加入DBU(4g)，室温下搅拌至反应结束。旋干过柱，得产品，收率41％。Compound 5 (6.24 g) was weighed into a reaction flask, and MeCN (62 mL) was added and stirred to dissolve. DBU (4 g) was added and stirred at room temperature until the end of the reaction. Spin the column and obtain the product with a yield of 41%.
方案2：Scenario 2:
Figure PCTCN2016093902-appb-000026
Figure PCTCN2016093902-appb-000026
称取化合物10(0.505g)加入反应瓶中，加入DCM(10mL)搅拌溶解。加入Dess-Martin氧化剂(0.8g)，Dess-Martin氧化剂与化合物10的摩尔比范围在1:1～3:1。室温下搅拌至反应结束。加入K2CO3水溶液和Brine淬灭反应，分液，水相用DCM萃取，合并有机相，无水硫酸镁干燥，过滤旋干过柱，得产品，收率 95％。Compound 10 (0.505 g) was weighed into a reaction flask, and dissolved by adding DCM (10 mL). Dess-Martin oxidant (0.8 g) was added and the molar ratio of Dess-Martin oxidant to compound 10 ranged from 1:1 to 3:1. Stir at room temperature until the end of the reaction. The reaction mixture was quenched by the addition of K 2 CO 3 aqueous solution and Brine, and the aqueous layer was separated and evaporated, and then evaporated.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.05–7.98(m,2H),7.60–7.49(m,1H),7.43(t,J＝7.7Hz,2H),6.54(d,J＝1.1Hz,1H),5.01(dd,J＝10.4,7.6Hz,1H),4.94(dd,J＝9.8,2.9Hz,1H),4.51(d,J＝7.6Hz,1H),4.15(d,J＝8.4Hz,1H),3.61(d,J＝6.9Hz,2H),3.15(d,J＝6.6Hz,1H),3.02–2.90(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 - 7.98 (m, 2H), 7.60 - 7.49 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H), 6.54 (d, J = 1.1 Hz, 1H) ), 5.01 (dd, J = 10.4, 7.6 Hz, 1H), 4.94 (dd, J = 9.8, 2.9 Hz, 1H), 4.51 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 8.4 Hz) , 1H), 3.61 (d, J = 6.9 Hz, 2H), 3.15 (d, J = 6.6 Hz, 1H), 3.02 - 2.90 (m, 1H).
实施例6，化合物5的制备。Example 6, Preparation of Compound 5.
Figure PCTCN2016093902-appb-000027
Figure PCTCN2016093902-appb-000027
称取化合物4(51g)加入反应瓶中，量取DCM(765mL)加入反应瓶，室温搅拌使其全溶。加入PCC(沙瑞特试剂)(45.8g)，该PCC与化合物4的摩尔比范围在1.5:1～5:1。置换惰性气体保护，室温搅拌反应。反应结束，加入饱和NaHCO3溶液，分液，水相用DCM萃取，合并有机相。有机相用饱和NaHCO3溶液、水、Brine洗，用无水Na2SO4干燥。有机相过滤，减压旋干，得化合物5粗品。纯化得产品，收率88％。Compound 4 (51 g) was weighed into a reaction flask, and DCM (765 mL) was weighed and added to the reaction flask, and the mixture was stirred at room temperature to be completely dissolved. PCC (Sharit reagent) (45.8 g) was added, and the molar ratio of PCC to compound 4 ranged from 1.5:1 to 5:1. Replace the inert gas protection and stir the reaction at room temperature. At the end of the reaction, a saturated NaHCO 3 solution was added, and the mixture was separated, and then the aqueous phase was extracted with DCM. The organic phase was washed with saturated NaHCO 3 solution, water and dried 2 SO 4, Brine washed, dried over anhydrous Na. The organic phase was filtered and dried under reduced pressure to give Compound 5 crude. The product was purified to give a yield of 88%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.06–7.99(m,2H),7.57(t,J＝7.4Hz,1H),7.44(t,J＝7.7Hz,2H),7.27(s,1H),5.00(ddd,J＝12.8,10.3,5.2Hz,2H),4.60(s,1H),4.54(d,J＝7.6Hz,1H),4.19(d,J＝7.8Hz,1H),3.73–3.54(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 - 7.79 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.27 (s, 1H), 5.00 (ddd, J = 12.8, 10.3, 5.2 Hz, 2H), 4.60 (s, 1H), 4.54 (d, J = 7.6 Hz, 1H), 4.19 (d, J = 7.8 Hz, 1H), 3.73 - 3.54 (m, 2H).
实施例7，化合物6的制备。Example 7, Preparation of Compound 6.
Figure PCTCN2016093902-appb-000028
Figure PCTCN2016093902-appb-000028
称取化合物5(1g)加入反应瓶中，量取DMF(8mL)加入反应瓶，置换惰性气体保护，室温搅拌使其全溶。转至-30℃低温浴槽中降温，加入DBU(0.23mL)，搅拌10min。内温-20℃左右时开始滴加NFSI(0.527g)的DMF(4mL)溶液，滴加完毕，低温下继续反应。NFSI与化合物5的摩尔比范围在1:1～3:1之间都可以使原料化合物5较好的转化。反应结束，加入水和DCM分液，水相用DCM萃取，合并有机相，有机相用水洗。无水硫酸镁干燥，过滤，旋干过柱得产品，收率73％。Compound 5 (1 g) was weighed into a reaction flask, and DMF (8 mL) was weighed and added to the reaction flask, and the mixture was replaced with an inert gas and stirred at room temperature to be completely dissolved. Turn to -30 ° C low temperature bath to cool, add DBU (0.23mL), stir for 10min. When the internal temperature was around -20 °C, a solution of NFSI (0.527 g) in DMF (4 mL) was added dropwise, and the addition was completed, and the reaction was continued at a low temperature. The raw material compound 5 can be preferably converted by a molar ratio of NFSI to compound 5 in the range of 1:1 to 3:1. At the end of the reaction, water and DCM were added and the aqueous phase was extracted with DCM. Dry over anhydrous magnesium sulfate, filter and spin dry to give a product, yield 73%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.10–7.99(m,2H),7.57(dd,J＝10.4,4.4Hz,1H),7.46(q,J＝7.3Hz,2H),5.02(dd,J＝10.5,7.6Hz,1H),4.96–4.87(m,1H),4.53(d,J＝7.5Hz,1H),4.46(s,1H),4.05(d,J＝9.0Hz,1H),3.59(dd,J＝9.1,6.0Hz,1H),3.35(ddd,J＝10.6,7.3,3.5Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 - 7.99 (m, 2H), 7.57 (dd, J = 10.4, 4.4 Hz, 1H), 7.46 (q, J = 7.3 Hz, 2H), 5.02 (dd, J =10.5, 7.6 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.53 (d, J = 7.5 Hz, 1H), 4.46 (s, 1H), 4.05 (d, J = 9.0 Hz, 1H), 3.59 (dd, J = 9.1, 6.0 Hz, 1H), 3.35 (ddd, J = 10.6, 7.3, 3.5 Hz, 1H).
实施例8，化合物7的制备。 Example 8, Preparation of Compound 7.
Figure PCTCN2016093902-appb-000029
Figure PCTCN2016093902-appb-000029
称取化合物6(1.01g)加入反应瓶中，量取DMF(10mL)加入反应瓶，置换惰性气体保护，室温搅拌使其全溶。转至-30℃低温浴槽中降温，加入DBU(0.42mL)，搅拌10min。内温降至-20℃时开始滴加NFSI(0.95g)的DMF溶液，滴加完毕，低温下继续反应至原料转化完全，NFSI与化合物5的摩尔比范围在1:1～3:1之间都可以使化合物5较好的转化搅拌反应。反应结束，加入水和DCM分液，水相用DCM萃取，合并有机相，有机相用水洗。无水硫酸镁干燥，过滤，旋干过柱得产品，收率52％。Compound 6 (1.01 g) was weighed into a reaction flask, and DMF (10 mL) was weighed and added to the reaction flask, and the mixture was replaced with an inert gas and stirred at room temperature to be completely dissolved. Turn to -30 ° C low temperature bath to cool, add DBU (0.42mL), stir for 10min. When the internal temperature drops to -20 °C, NFSI (0.95g) DMF solution is added dropwise. After the addition is completed, the reaction is continued at low temperature until the conversion of the starting material is complete. The molar ratio of NFSI to compound 5 ranges from 1:1 to 3:1. Compound 5 can be better converted to a stirred reaction. At the end of the reaction, water and DCM were added and the aqueous phase was extracted with DCM. Dry over anhydrous magnesium sulfate, filter and spin dry the product to give a yield of 52%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.08–8.00(m,2H),7.56(t,J＝7.4Hz,1H),7.44(t,J＝7.7Hz,2H),6.44(d,J＝1.3Hz,1H),5.07–4.94(m,2H),4.54(d,J＝7.5Hz,1H),4.02(d,J＝9.8Hz,1H),3.59(dd,J＝10.1,5.2Hz,1H),3.43–3.29(m,1H),3.00(d,J＝12.4Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 - 8.00 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 6.44 (d, J = 1.3) Hz, 1H), 5.07–4.94 (m, 2H), 4.54 (d, J = 7.5 Hz, 1H), 4.02 (d, J = 9.8 Hz, 1H), 3.59 (dd, J = 10.1, 5.2 Hz, 1H) ), 3.43 - 3.29 (m, 1H), 3.00 (d, J = 12.4 Hz, 1H).
实施例9，化合物8的制备。Example 9, Preparation of Compound 8.
方案1：plan 1:
Figure PCTCN2016093902-appb-000030
Figure PCTCN2016093902-appb-000030
称取化合物6(3.24g)加入反应瓶中，量取MeCN(32.4mL)加入反应瓶，置换惰性气体保护，室温搅拌使其全溶。加入DBU(1.86mL)，室温搅拌反应，得化合物7(化合物7过柱提纯测试NMR)。加入CDI(2.14g)，室温下继续反应。旋干过柱纯化，得产品，两步收率67％。Compound 6 (3.24 g) was weighed into a reaction flask, and MeCN (32.4 mL) was weighed and added to the reaction flask, and the mixture was replaced with an inert gas and stirred at room temperature to be completely dissolved. DBU (1.86 mL) was added, and the reaction was stirred at room temperature to give Compound 7 (Comp. CDI (2.14 g) was added and the reaction was continued at room temperature. The product was purified by spin-drying to obtain a product, and the yield in two steps was 67%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.05(dd,J＝11.8,4.7Hz,3H),7.60–7.53(m,1H),7.45(t,J＝7.6Hz,2H),7.36(t,J＝1.4Hz,1H),7.07(dd,J＝1.6,0.8Hz,1H),6.67(s,1H),5.60–5.42(m,1H),5.02(dd,J＝10.6,7.5Hz,1H),4.54(d,J＝7.5Hz,1H),4.02(d,J＝8.7Hz,1H),3.57(dd,J＝9.3,6.2Hz,1H),3.36(s,1H),3.03(s,1H)。 1 H NMR (400MHz, CDCl3) δ8.05 (dd, J = 11.8,4.7Hz, 3H), 7.60-7.53 (m, 1H), 7.45 (t, J = 7.6Hz, 2H), 7.36 (t, J = 1.4 Hz, 1H), 7.07 (dd, J = 1.6, 0.8 Hz, 1H), 6.67 (s, 1H), 5.60 - 5.42 (m, 1H), 5.02 (dd, J = 10.6, 7.5 Hz, 1H) , 4.54 (d, J = 7.5 Hz, 1H), 4.02 (d, J = 8.7 Hz, 1H), 3.57 (dd, J = 9.3, 6.2 Hz, 1H), 3.36 (s, 1H), 3.03 (s, 1H).
方案2：Scenario 2:
Figure PCTCN2016093902-appb-000031
Figure PCTCN2016093902-appb-000031
称取化合物7(236mg)加入反应瓶中，加入THF(2.5mL)搅拌溶解，加入DBU(53uL)，搅拌反应10min。加入CDI(243mg)，继续搅拌反应。反应结束，加入EA和水分液，水相用EA萃取，合并有机相，有机相用 Brine洗，无水硫酸镁干燥过滤旋干过柱得产品，收率82％。Compound 7 (236 mg) was weighed into a reaction flask, and dissolved by adding THF (2.5 mL), DBU (53 uL) was added, and the reaction was stirred for 10 min. CDI (243 mg) was added and the reaction was stirred. At the end of the reaction, EA and water are added, the aqueous phase is extracted with EA, the organic phase is combined, and the organic phase is used. The mixture was washed with Brine, dried over anhydrous magnesium sulfate and filtered to dryness to afford product, yield 82%.
实施例10，化合物9的制备。Example 10, Preparation of Compound 9.
Figure PCTCN2016093902-appb-000032
Figure PCTCN2016093902-appb-000032
称取化合物8(1.51g)加入反应瓶中，量取MeCN(22.7ml)加入反应瓶，置换惰性气体保护，搅拌溶解。加入侧链化合物12(0.53g)，加入DBU室温搅拌反应，化合物8与化合物12的摩尔比范围是1:1～1:3。反应结束，旋干过柱纯化，得产品，收率68％。Compound 8 (1.51 g) was weighed into a reaction flask, and MeCN (22.7 ml) was weighed into a reaction flask, replaced with an inert gas, and dissolved by stirring. The side chain compound 12 (0.53 g) was added, and the reaction was stirred by adding DBU at room temperature, and the molar ratio of the compound 8 to the compound 12 was in the range of 1:1 to 1:3. The reaction was completed, and the product was purified by spin-drying to give a product, yield 68%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.10–7.98(m,2H),7.79(s,1H),7.57(d,J＝7.4Hz,1H),7.45(t,J＝7.7Hz,2H),7.27(s,1H),7.19–7.14(m,2H),6.64(d,J＝6.7Hz,1H),5.02(dd,J＝10.5,7.6Hz,1H),4.84(dd,J＝10.3,2.1Hz,1H),4.53(d,J＝7.5Hz,1H),4.40(t,J＝7.2Hz,2H),4.09(d,J＝9.4Hz,1H),3.87–3.70(m,3H),3.61(dt,J＝12.6,6.5Hz,2H),3.41(s,1H),3.30(ddd,J＝10.5,7.1,3.3Hz,1H),3.07(q,J＝7.0Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 - 7.98 (m, 2H), 7.79 (s, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.27(s,1H), 7.19–7.14(m,2H), 6.64(d,J=6.7Hz,1H), 5.02(dd,J=10.5,7.6Hz,1H),4.84(dd,J=10.3, 2.1 Hz, 1H), 4.53 (d, J = 7.5 Hz, 1H), 4.40 (t, J = 7.2 Hz, 2H), 4.09 (d, J = 9.4 Hz, 1H), 3.87 - 3.70 (m, 3H) , 3.61 (dt, J = 12.6, 6.5 Hz, 2H), 3.41 (s, 1H), 3.30 (ddd, J = 10.5, 7.1, 3.3 Hz, 1H), 3.07 (q, J = 7.0 Hz, 1H).
实施例11，Solithromycin的制备。Example 11, Preparation of Solithromycin.
Figure PCTCN2016093902-appb-000033
Figure PCTCN2016093902-appb-000033
称取化合物9(0.7g)加入反应瓶中，置换惰性气体保护，量取MeOH(3.5mL)加入反应瓶，搅拌溶解。加入NH3·MeOH(3.5mL)溶液，室温搅拌反应。反应结束，旋干过柱纯化，得产品，收率75％。Compound 9 (0.7 g) was weighed into a reaction flask, replaced with an inert gas, and MeOH (3.5 mL) was added to the reaction flask and stirred to dissolve. A solution of NH3.MeOH (3.5 mL) was added and the mixture was stirred at room temperature. The reaction was completed, and the product was purified by spin-drying to give a product, yield 75%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.27(s,1H),7.18(d,J＝6.6Hz,2H),6.64(dt,J＝6.7,2.4Hz,1H),4.93–4.82(m,1H),4.42(t,J＝7.3Hz,2H),4.30(d,J＝7.3Hz,1H),4.07(d,J＝10.4Hz,1H),3.82–3.70(m,2H),3.68–3.58(m,1H),3.58–3.46(m,3H),3.44(s,1H),3.15(ddd,J＝20.8,12.0,7.1Hz,2H)。 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.27 (s, 1H), 7.18 (d, J = 6.6Hz, 2H), 6.64 (dt, J = 6.7,2.4Hz, 1H), 4.93–4.82 (m,1H), 4.42 (t, J=7.3 Hz, 2H), 4.30 (d, J=7.3 Hz, 1H), 4.07 (d, J = 10.4 Hz, 1H), 3.82–3.70 (m) , 2H), 3.68 - 3.58 (m, 1H), 3.58 - 3.46 (m, 3H), 3.44 (s, 1H), 3.15 (ddd, J = 20.8, 12.0, 7.1 Hz, 2H).
实施例12，化合物3′的制备。 Example 12, Preparation of Compound 3'.
Figure PCTCN2016093902-appb-000034
Figure PCTCN2016093902-appb-000034
称取化合物2(10g)加入反应瓶中，置换惰性气体保护，加入DCM(100mL)，乙酸酐(3.6mL)，室温下搅拌反应。待反应完全，加入饱和NaHCO3淬灭反应，分液，萃取，旋干过柱纯化，得产品化合物3′，收率70％。Compound 2 (10 g) was weighed into a reaction flask, replaced with an inert gas, and DCM (100 mL), acetic anhydride (3.6 mL) was added, and the mixture was stirred at room temperature. After the reaction is completed, the reaction is quenched by the addition of saturated NaHCO 3 , liquid separation, extraction, and spin-drying to purify to give the product compound 3', yield 70%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ5.17(dd,J＝11.1,2.4Hz,1H),4.75(dd,J＝10.5,7.6Hz,1H),4.61(d,J＝7.6Hz,1H),3.94(s,1H),3.83(d,J＝1.5Hz,1H),3.72(d,J＝2.7Hz,1H),3.54–3.42(m,2H),3.26(s,1H),3.06–2.96(m,1H)。1H NMR (400MHz, CDCl3) δ 5.17 (dd, J = 11.1, 2.4 Hz, 1H), 4.75 (dd, J = 10.5, 7.6 Hz, 1H), 4.61 (d, J = 7.6 Hz, 1H), 3.94 (s, 1H), 3.83 (d, J = 1.5 Hz, 1H), 3.72 (d, J = 2.7 Hz, 1H), 3.54 - 3.42 (m, 2H), 3.26 (s, 1H), 3.06 - 2.96 ( m, 1H).
实施例13，化合物4′的制备。Example 13, Preparation of Compound 4'.
Figure PCTCN2016093902-appb-000035
Figure PCTCN2016093902-appb-000035
称取化合物3′(1g)加入至干燥的反应瓶中，置换惰性气体保护，加入DCM(8mL)，将内外降至0℃以下，加入吡啶(1.02mL)，搅拌20min。滴加BTC(0.7g)的DCM(2mL)溶液，滴加过程控制内温不高于0℃，滴加完毕转至室温反应。反应结束，加入水淬灭反应，分液，萃取，旋干过柱纯化，得产品化合物4′，收率70％。The compound 3' (1 g) was weighed and added to a dry reaction flask, and the mixture was replaced with an inert gas. DCM (8 mL) was added, and the mixture was cooled to below 0 ° C. pyridine (1.02 mL) was added and stirred for 20 min. A solution of BTC (0.7 g) in DCM (2 mL) was added dropwise, and the internal temperature of the dropwise addition process was not higher than 0 ° C, and the mixture was transferred to room temperature for reaction. After completion of the reaction, the reaction was quenched by adding water, liquid separation, extraction, and spin-drying to purify to give the product compound 4', yield 70%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ5.13(dd,J＝10.7,2.5Hz,1H),4.81–4.67(m,2H),4.59(d,J＝7.6Hz,1H),3.70(d,J＝2.6Hz,1H),3.48(dt,J＝12.0,3.7Hz,2H),3.01-2.93(m,1H),2.92(s,3H)。 1 H NMR (400MHz, CDCl3) δ5.13 (dd, J = 10.7,2.5Hz, 1H), 4.81-4.67 (m, 2H), 4.59 (d, J = 7.6Hz, 1H), 3.70 (d, J = 2.6 Hz, 1H), 3.48 (dt, J = 12.0, 3.7 Hz, 2H), 3.01-2.93 (m, 1H), 2.92 (s, 3H).
实施例14，化合物5′的制备。Example 14, Preparation of Compound 5'.
Figure PCTCN2016093902-appb-000036
Figure PCTCN2016093902-appb-000036
称取化合物4′(3.2g)加入至干燥的反应瓶中，置换惰性气体保护，加入DCM(32mL)，加入PCC氧化剂(2.62g)，室温搅拌反应。反应结束，过滤，加入水相洗涤有机相，分液，萃取，旋干过柱纯化，得产品化合物5′，收率71％。 Compound 4' (3.2 g) was weighed into a dry reaction flask, replaced with an inert gas, and DCM (32 mL) was added, and a PCC oxidant (2.62 g) was added, and the reaction was stirred at room temperature. After completion of the reaction, the mixture was filtered, and the organic phase was washed with an aqueous phase, and the mixture was separated, extracted, and purified by spin-drying to give the product compound 5', yield 71%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ5.01(dd,J＝10.1,2.8Hz,1H),4.73(dd,J＝10.6,7.6Hz,1H),4.64(d,J＝1.0Hz,1H),4.38(d,J＝7.6Hz,1H),4.17(d,J＝7.8Hz,1H),3.80(q,J＝6.8Hz,1H),3.60–3.47(m,1H),3.07–2.90(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ5.01 (dd, J = 10.1,2.8Hz, 1H), 4.73 (dd, J = 10.6,7.6Hz, 1H), 4.64 (d, J = 1.0Hz, 1H) , 4.38 (d, J = 7.6 Hz, 1H), 4.17 (d, J = 7.8 Hz, 1H), 3.80 (q, J = 6.8 Hz, 1H), 3.60 - 3.47 (m, 1H), 3.07 - 2.90 ( m, 2H).
实施例15，化合物6′的制备。Example 15, Preparation of Compound 6'.
Figure PCTCN2016093902-appb-000037
Figure PCTCN2016093902-appb-000037
称取化合物5′(1.5g)加入至干燥的反应瓶中，置换惰性气体保护，加入DMF(12mL)，体系降温，加入DBU(0.42mL)，搅拌20min。内外降至-15℃以下时，滴加NFSI(0.94g)的DMF(6mL)溶液。滴加完毕，低温下搅拌反应。反应结束，加入水和DCM分液，萃取，旋干过柱，得产品化合物6′，收率67％。Compound 5' (1.5 g) was weighed into a dry reaction flask, replaced with an inert gas, DMF (12 mL) was added, the system was cooled, DBU (0.42 mL) was added and stirred for 20 min. When the inside and the outside fell below -15 ° C, a solution of NFSI (0.94 g) in DMF (6 mL) was added dropwise. After the dropwise addition is completed, the reaction is stirred at a low temperature. At the end of the reaction, water and DCM were added to separate portions, and the mixture was extracted and dried to give a product compound 6', yield 67%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ4.95(dd,J＝9.6,3.0Hz,1H),4.74(dd,J＝10.6,7.6Hz,1H),4.48(s,1H),4.38(d,J＝7.6Hz,1H),4.02(dd,J＝10.5,1.5Hz,1H),3.58–3.41(m,2H),3.04–2.92(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ4.95 (dd, J = 9.6,3.0Hz, 1H), 4.74 (dd, J = 10.6,7.6Hz, 1H), 4.48 (s, 1H), 4.38 (d, J = 7.6 Hz, 1H), 4.02 (dd, J = 10.5, 1.5 Hz, 1H), 3.58 - 3.41 (m, 2H), 3.04 - 2.92 (m, 1H).
实施例16，化合物8′的制备。Example 16, Preparation of Compound 8'.
Figure PCTCN2016093902-appb-000038
Figure PCTCN2016093902-appb-000038
称取化合物6′(0.6g)加入反应瓶中，量取MeCN(6mL)加入反应瓶，置换惰性气体保护，室温搅拌使其全溶。加入DBU(0.38mL)，室温搅拌反应至原料消耗完全，得化合物7′。加入CDI(0.43g)，室温下继续反应得化合物8′。旋干过柱纯化，得产品化合物8′，两步收率67％。The compound 6' (0.6 g) was weighed into a reaction flask, and MeCN (6 mL) was weighed into a reaction flask, replaced with an inert gas, and stirred at room temperature to be completely dissolved. DBU (0.38 mL) was added, and the reaction was stirred at room temperature until the starting material was consumed to give compound 7'. CDI (0.43 g) was added and the reaction was continued at room temperature to give compound 8'. The product was purified by spin-drying to give the product compound 8' in a two-step yield of 67%.
核磁数据如下：The nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl3)δ8.15–8.01(m,1H),7.37(t,J＝1.4Hz,1H),7.07(dd,J＝1.6,0.8Hz,1H),6.70(s,1H),5.55(dd,J＝9.3,3.3Hz,1H),4.74(dd,J＝10.5,7.6Hz,1H),4.39(d,J＝7.6Hz,1H),3.99(dd,J＝9.9,1.2Hz,1H),3.48(m,2H),3.14-2.92(br,1H)。 1 H NMR (400MHz, CDCl3) δ8.15-8.01 (m, 1H), 7.37 (t, J = 1.4Hz, 1H), 7.07 (dd, J = 1.6,0.8Hz, 1H), 6.70 (s, 1H ), 5.55 (dd, J = 9.3, 3.3 Hz, 1H), 4.74 (dd, J = 10.5, 7.6 Hz, 1H), 4.39 (d, J = 7.6 Hz, 1H), 3.99 (dd, J = 9.9, 1.2 Hz, 1H), 3.48 (m, 2H), 3.14 - 2.92 (br, 1H).
综上，本发明Solithromycin的制备反应路线可优选为以下三条路线： In summary, the preparation route of the Solithromycin of the present invention can be preferably the following three routes:
路线一：Route 1:
Figure PCTCN2016093902-appb-000039
Figure PCTCN2016093902-appb-000039
路线二：Route 2:
Figure PCTCN2016093902-appb-000040
Figure PCTCN2016093902-appb-000040
路线三：Route 3:
Figure PCTCN2016093902-appb-000041
Figure PCTCN2016093902-appb-000041
上述三条Solithromycin的反应路线中具体反应步骤，均在前述实施例中已作出说明，故不在此赘述。The specific reaction steps in the reaction routes of the above three Solithromycins have been described in the foregoing examples, and thus will not be described herein.
以上对本发明做了详尽的描述，其目的在于让熟悉此领域技术的人士能够了解本发明的内容并加以实施，并不能以此限制本发明的保护范围，凡根据本发明的精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围内。 The present invention has been described in detail above, and is intended to be understood by those skilled in the art of the invention. Modifications or modifications are intended to be included within the scope of the invention.

Claims (10)

  1. 具有如下通式I结构的酮内酯抗生素中间体及其盐、溶剂合物、多晶型物：Ketolide antibiotic intermediates having the structure of the general formula I and salts, solvates, polymorphs thereof:
    Figure PCTCN2016093902-appb-100001
    Figure PCTCN2016093902-appb-100001
    其中，among them,
    R为H、
    Figure PCTCN2016093902-appb-100002
    或-COOH，    R is H,
    Figure PCTCN2016093902-appb-100002
    Or -COOH,
    R1为苯基、取代的芳香基或C2～C6烷基。R 1 is a phenyl group, a substituted aryl group or a C 2 -C 6 alkyl group.
  2. 如权利要求1所述酮内酯抗生素中间体I及其盐、溶剂合物、多晶型物，其特征在于可通过化合物Ia发生消除反应得到，化合物Ia结构式如下所示：The ketolide antibiotic intermediate I according to claim 1 and a salt, solvate or polymorph thereof, which are obtained by the elimination reaction of the compound Ia, and the structural formula of the compound Ia is as follows:
    Figure PCTCN2016093902-appb-100003
    Figure PCTCN2016093902-appb-100003
    其中，R1为苯基、取代的芳香基或C2～C6烷基。Wherein R 1 is a phenyl group, a substituted aryl group or a C 2 -C 6 alkyl group.
  3. 一种权利要求1所述酮内酯抗生素中间体及其盐、溶剂合物、多晶型物的制备方法，其特征在于包括下述步骤：化合物I4经3-位羟基氧化反应，2-位氟取代反应，11-位、12-位消除反应制备得化合物I7，A method for preparing a ketolide antibiotic intermediate according to claim 1 and a salt, a solvate thereof and a polymorph thereof, comprising the steps of: subjecting compound I4 to 3-position hydroxy oxidation reaction, 2-position Fluorine substitution reaction, 11-position, 12-position elimination reaction to prepare compound I7,
    Figure PCTCN2016093902-appb-100004
    Figure PCTCN2016093902-appb-100004
    其中，R1为苯基、取代的芳香基或C2～C6烷基。Wherein R 1 is a phenyl group, a substituted aryl group or a C 2 -C 6 alkyl group.
  4. 如权利要求3所述制备方法，其特征在于包括如下步骤： The preparation method according to claim 3, comprising the steps of:
    Figure PCTCN2016093902-appb-100005
    Figure PCTCN2016093902-appb-100005
    步骤一，化合物I4在室温或低温、氧化剂存在条件下反应制备化合物I5，其中，氧化剂与化合物I4的摩尔比范围是1:1～3:1；Step 1, the compound I4 is prepared at room temperature or low temperature, in the presence of an oxidizing agent to prepare a compound I5, wherein the molar ratio of the oxidizing agent to the compound I4 is 1:1 ~ 3:1;
    步骤二，化合物I5在-50～50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF氟试剂条件下反应制备化合物I6，其中，氟试剂与化合物I5的摩尔比范围是1:1～3:1；Step 2: Compound I5 is prepared by reacting compound I5 at -50 to 50 ° C, DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS in one or more alkaline environments, SelectFluor, NFSI or TBAF fluorine reagent, wherein The molar ratio of the fluorine reagent to the compound I5 is in the range of 1:1 to 3:1;
    步骤三，化合物I6在有机溶剂中，在DBU、NaH碱性条件反应制备得化合物I7；Step 3, the compound I6 is prepared in an organic solvent under DBU, NaH basic conditions to obtain the compound I7;
    其中，R1为苯基、取代的芳香基或C2～C6烷基。Wherein R 1 is a phenyl group, a substituted aryl group or a C 2 -C 6 alkyl group.
  5. 如权利要求3所述制备方法，其特征在于包括如下步骤：The preparation method according to claim 3, comprising the steps of:
    Figure PCTCN2016093902-appb-100006
    Figure PCTCN2016093902-appb-100006
    步骤一，化合物I4在有机溶剂中，在碱性条件反应制备得化合物10；Step 1, the compound I4 is prepared in an organic solvent under basic conditions to obtain the compound 10;
    步骤二，化合物I10在室温、氧化条件下反应制备化合物I11，其中，氧化剂与化合物I10的摩尔比范围是1:1～3:1；Step 2, the compound I10 is reacted at room temperature under oxidizing conditions to prepare a compound I11, wherein the molar ratio of the oxidizing agent to the compound I10 is in the range of 1:1 to 3:1;
    步骤三，化合物I11在50～-50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF氟试剂条件下反应制备化合物I7，氟试剂与化合物I11的摩尔比范围是1:1～3:1； Step 3: Compound I11 is prepared by reacting one or more alkaline environments of DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS in a basic environment of 50--50 ° C, SelectFluor, NFSI or TBAF fluorine reagent. The molar ratio of the reagent to the compound I11 is in the range of 1:1 to 3:1;
    其中，R1为苯基、取代的芳香基或C2～C6烷基。Wherein R 1 is a phenyl group, a substituted aryl group or a C 2 -C 6 alkyl group.
  6. 如权利要求3所述制备方法，其特征在于包括如下步骤：The preparation method according to claim 3, comprising the steps of:
    Figure PCTCN2016093902-appb-100007
    Figure PCTCN2016093902-appb-100007
    步骤一，化合物I4在氧化条件下反应制备化合物I5，其中，沙瑞特试剂与化合物I4的摩尔比范围2:1～5:1；Step 1, the compound I4 is reacted under oxidizing conditions to prepare the compound I5, wherein the molar ratio of the Sharit reagent to the compound I4 ranges from 2:1 to 5:1;
    步骤二，化合物I5在有机溶剂中，在DBU、NaH碱性条件反应制备得化合物I11；Step 2, the compound I5 is prepared in an organic solvent under DBU, NaH basic conditions to obtain the compound I11;
    步骤三，化合物I11在-50～50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF氟试剂条件下反应制备化合物I7，氟试剂与化合物I11的摩尔比范围是1:1～3:1；Step 3: Compound I11 is prepared by reacting one or more alkaline environments of DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS at -50 to 50 ° C under the conditions of SelectFluor, NFSI or TBAF fluorine reagent. The molar ratio of the reagent to the compound I11 is in the range of 1:1 to 3:1;
    其中，R1为苯基、取代的芳香基或C2～C6烷基。Wherein R 1 is a phenyl group, a substituted aryl group or a C 2 -C 6 alkyl group.
  7. 一种权利要求1所述酮内酯抗生素中间体的制备方法，其特征在于包括下述步骤：化合物I6经12-位消除反应制备得化合物I7，A method for preparing a ketolide antibiotic intermediate according to claim 1, which comprises the steps of: preparing compound I7 by a 12-position elimination reaction of compound I6,
    Figure PCTCN2016093902-appb-100008
    Figure PCTCN2016093902-appb-100008
    其中，化合物6在有机溶剂中，DBU、NaH碱性条件反应制备得化合物7，所述R1包括苯基、取代的芳香基或C1～C6烷基。Among them, the compound 6 is prepared by reacting DBU and NaH under basic conditions in an organic solvent, and the R 1 includes a phenyl group, a substituted aryl group or a C1-C6 alkyl group.
  8. 一如权利要求1所述酮内酯抗生素中间体的制备方法，其特征在于包括下述步骤：化合物I11经2-位氟取代反应制备得化合物I7， A method for preparing a ketolide antibiotic intermediate according to claim 1, which comprises the steps of: compound I11 is prepared by a 2-position fluorine substitution reaction;
    Figure PCTCN2016093902-appb-100009
    Figure PCTCN2016093902-appb-100009
    化合物I11在50～-50℃，DBU、NaH、KH、tBuONa、tBuOK、NaHMDS或KHMDS中一种或多种碱性环境，SelectFluor、NFSI或TBAF氟试剂条件下反应制备化合物I7，氟试剂与化合物I11的摩尔比范围是1:1～3:1,所述R1为苯基、取代的芳香基或C1～C6烷基。Compound I11 is prepared by reacting one or more alkaline environments of DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS in a basic environment of 50--50 ° C, SelectFluor, NFSI or TBAF fluorine reagent, fluorine reagent and compound The molar ratio of I11 ranges from 1:1 to 3:1, and R 1 is a phenyl group, a substituted aryl group or a C1-C6 alkyl group.
  9. 一种权利要求1所述酮内酯抗生素中间体的制备方法，其特征在于包括下述步骤：R为
    Figure PCTCN2016093902-appb-100010
    的化合物I8，由化合物I7制备而得：    A method for preparing a ketolide antibiotic intermediate according to claim 1, which comprises the steps of: R is
    Figure PCTCN2016093902-appb-100010
    Compound I8, prepared from compound I7:
    Figure PCTCN2016093902-appb-100011
    Figure PCTCN2016093902-appb-100011
    其中，化合物I7在室温及DBU碱性条件下反应制备化合物8，所述R1为苯基、取代的芳香基或C1～C6烷基。Wherein the compound I7 prepared by reacting a compound of DBU at room temperature under basic conditions to 8, R 1 is a phenyl group, a substituted aromatic group or a C1 ~ C6 alkyl group.
  10. 一种化合物Solithromycin的制备方法，包括如下步骤：A method for preparing a compound Solithromycin, comprising the following steps:
    Figure PCTCN2016093902-appb-100012
    Figure PCTCN2016093902-appb-100012
    化合物I8与化合物12取代成环反应后制备化合物I9，化合物I9水解制备得化合物Solithromycin，所述R1为苯基、取代的芳香基或C1～C6烷基,化合物I8与化合物12的摩尔比范围是1:1～1:3，化合物I8与化合物I12在有机溶剂中、DBU催化条件下制备得到化合物I9。 Compound I8 is compounded with compound 12 to form a compound I9, and compound I9 is hydrolyzed to obtain a compound Solithromycin. The R1 is a phenyl group, a substituted aryl group or a C1-C6 alkyl group, and the molar ratio range of the compound I8 to the compound 12 is 1:1 to 1:3, compound I8 and compound I12 are prepared in an organic solvent under the conditions of DBU catalysis to obtain compound I9.
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