CN108610388B

CN108610388B - Preparation method of macrolide

Info

Publication number: CN108610388B
Application number: CN201611135959.1A
Authority: CN
Inventors: 徐辉; 雷平生; 赵哲辉; 徐苗焕; 陈鉴东; 侯建
Original assignee: Shanghai Jingxin Biological Medical Co ltd; Zhejiang Jingxin Pharmaceutical Co Ltd
Current assignee: Shanghai Jingxin Biological Medical Co ltd; Zhejiang Jingxin Pharmaceutical Co Ltd
Priority date: 2016-12-12
Filing date: 2016-12-12
Publication date: 2020-11-06
Anticipated expiration: 2036-12-12
Also published as: CN108610388A

Abstract

The invention discloses a preparation method of macrolide, which is characterized in that firstly, a hydroxyl protecting group is removed, and then, a side chain compound is directly connected with a closed ring to obtain the macrolide. The reaction avoids the defects that the last step of removing the sugar hydroxyl protecting group in the prior art is easy to generate side reaction and generate impurities which are difficult to remove and purify. Therefore, the macrolide (especially the solithromycin) obtained by the method has higher purity, fewer side reactions, convenient post-treatment and safe operation, and is suitable for large-scale production.

Description

Preparation method of macrolide

Technical Field

The invention belongs to the field of medicine synthesis, and relates to a preparation method of macrolide.

Background

Macrolides are well known for use in the treatment of a variety of infectious diseases, and are effective in the treatment and prevention of infections caused by a broad spectrum of bacterial and protozoan pathogens, and they are also useful in the treatment of respiratory and soft tissue infections. Macrolide compounds are characterized by the presence of a large lactone ring, which is typically a 14-, 15-or 16-membered macrolide to which one or more sugars may be attached, including deoxy sugars such as cladinose and desosamine. Erythromycin is the first such compound introduced into clinical practice, whose molecular structure comprises a 14-membered macrolide of two sugar moieties, which contains a ketolide ring moiety within the molecule. Thus, ketolides represent a newer class of macrolide antibiotics, which have attracted much attention for their acid stability and superior drug utility.

Solithromycin (also known as CEM-101, OPT-1068, CAS No. 760981-83-7) is a third generation macrolide antibiotic drug developed by cemdra pharmaceutical company for the treatment of community-acquired bacterial pneumonia (CABP) and is currently in the key phase III clinical trial. The solithromycin is the first fluorine-containing substituted macrolide drug entering clinic, and is also a macrolide antibiotic which can be orally and intravenously administrated after azithromycin, and the structure of the antibiotic is shown as the following formula IA:

the prior art reports about synthetic routes of solithromycin. WO 2009055557A1 discloses a synthetic route to solithromycin IA starting from clarithromycin, as shown in scheme 1, wherein clarithromycin is first protected at the sugar hydroxyl group by an acyl group (e.g., benzoyl Bz) and then reacted with the sterically hindered hydroxyl activator Carbonyldiimidazole (CDI) to form intermediate CL-1; then generating an azide-containing oxazole ring intermediate CL-2 with azidobutylamine; then removing one glycosyl group under the acidic condition to form an intermediate CL-3; oxidizing the hydroxyl formed after removing glycosyl by using an oxidant to form an intermediate CL-4; then F substitution is carried out at the ortho position through fluorination reaction to form an intermediate CL-5; and finally, forming triazole with aromatic alkyne, and removing a sugar hydroxyl protecting group to form the target solithromycin IA. WO 2010048599A1 has adjusted the route, namely, in the process of preparing CL-2 from CL-1, 4-aminobutanol is used as a raw material, then hydroxyl is converted into azide groups, and then the azide groups react according to the original route. However, the process route still has long reaction steps, and the reaction of desugaring, oxidation and the like on the intermediate containing azide is dangerous to operate (the azide compounds are all easily explosive and toxic compounds); meanwhile, the azide intermediate and the alkynes have more side reactions in the step of generating the five-membered ring triazole through ring closing, so the azide intermediate and the alkynes are not suitable for industrial large-scale production.

WO 2014145210A1 optimizes the above route in order to reduce the reaction steps, and adopts a mode of directly introducing raw materials of five-membered ring triazole with a side chain as shown in a route 2. The specific synthesis steps comprise: preparing an intermediate CL-1 from clarithromycin, then butting with a side chain of five-membered ring triazole to form an oxazole ring intermediate (wherein CP is amino, protected amino or nitro), then sequentially carrying out steps of desugaring, oxidation, fluorination and the like, and finally adopting a corresponding method according to a CP group to form amino, thereby obtaining the solithromycin IA. Although the reaction steps are reduced without introducing azido group and performing a ring closing step with alkyne, the solubility of the reaction raw materials and partial intermediates in organic reaction is reduced along with the increase of the molecular weight of the reaction raw materials and partial intermediates, the reaction post-treatment is influenced, and side chain five-membered ring triazole needs to undergo steps of desugaring, oxidation and the like, so that more side reactions are easily generated, and the large-scale production is difficult.

CN 104650166a discloses another preparation method of solithromycin, which is shown in scheme 3, and comprises preparing an intermediate II by desugaring and oxidizing, then forming an oxazole ring by docking with a five-membered ring triazole side chain in the same manner as in scheme 2, and finally forming solithromycin IA by fluoro and desugaring a hydroxyl protecting group. The method avoids the steps of desugaring and oxidizing the side chain five-membered ring triazole, and reduces the occurrence of side reactions. But the solubility of the compound intermediate II after desugarization and oxidation is lower than that of the intermediate CL-1, so that the reaction is difficult and the conversion rate is low; in addition, when the exposed amino group is subjected to deprotection, impurities shown in the following formulas 1 and 2 are generated, the impurities are generated when the amino triazole side chain and methyl benzoate (or methyl acetate) are subjected to acylation side reaction, not only is the cost increased due to the excessive consumption of the amino side chain, but also the quality of a finished product of the solithromycin IA is influenced due to the fact that the side chain is difficult to purify.

Disclosure of Invention

In order to reduce the dangerous and/or toxic operation steps in the existing synthetic route of macrolide compounds (particularly solithromycin), reduce the occurrence of side reactions, improve the quality and reaction efficiency of target products, reduce the production cost and realize industrial large-scale production, the invention provides a new synthetic process route of macrolide compounds to make up for the defects of the prior art.

The invention adopts the following technical scheme to achieve the purpose.

Specifically, the invention provides an improved preparation method of macrolide, the synthetic route of which is shown as follows, wherein firstly, the compound shown as the formula III is subjected to desugar hydroxyl protection to obtain the compound shown as the formula IV, and then the macrolide shown as the formula I is obtained through the side chain reaction to a related ring. The reaction avoids the defect that impurities which are difficult to remove and purify are generated due to side reaction caused by the protection of desugared hydroxyl after ring closing in the prior art. Therefore, the macrolide compound (especially solithromycin IA) obtained by the method has higher purity, fewer side reactions, convenient post-treatment and safe operation, and is suitable for large-scale production.

Wherein R is a sugar hydroxyl protecting group, e.g., an acyl protecting group such as a substituted or unsubstituted alkylacyl, arylacyl, heteroarylacyl, aralkylacyl or heteroaralkylacyl group, said substituent being C₁-C₄Alkyl or halogen, R is preferably benzoyl or acetyl.

X is H; y is OR¹Wherein R is¹Is H, a monosaccharide, disaccharide, polysaccharide or alkyl group, e.g. a monosaccharide containing a protected or unprotected 2' -hydroxy group, wherein the protecting group is a sterically hindered acyl group, e.g. a substituted or unsubstituted alkylacyl, arylacyl, heteroarylacyl, aralkanoyl or heteroaralkylacyl group, the substituent being C₁-C₄Alkyl or halogen; or X, Y with attached carbon oneTo form carbonyl-C ═ O.

W is H, halogen or OH, preferably halogen, such as F, Cl, Br, I, more preferably F or Cl.

A. B together form- (CH)₂)_nWherein n is an integer of 1-10, preferably an integer of 1-4, more preferably 1, 2, 3 or 4; or A, B together form an unsaturated hydrocarbyl group containing 2 to 10 carbons, preferably 2 to 5 carbons.

C is substituted or unsubstituted aminoaryl, aminoarylalkyl or alkylaminoaryl, the substituent being C₁-C₄Alkyl or halogen, C is preferably aminophenyl, aminobenzyl, methylaminophenyl.

The desugared hydroxyl protection refers to the removal of the hydroxyl protecting group on the sugar unit fragment, and can be performed in a manner of removing the sugar protecting group in some conventional sugar chemistry, for example, the sugar hydroxyl protecting group is removed from the compound of formula III in an alcohol solvent under the conditions from room temperature to reflux, so as to obtain the compound of formula IV. The alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol and n-butanol.

In the side chain-to-ring reaction, the compound of formula IV can be prepared by side chain-to-ring reaction with the compound of formula VA to prepare the compound of formula I.

Wherein CP is amino, amino protecting group selected from Boc, BsMoc, Trityl or MeOTTRYL, or nitro, A, B are as defined above.

When CP is amino, the compound of formula IV and the compound of formula VA are subjected to side chain reaction to form the macrolide of formula I directly.

When CP is amino protecting group, the compound of formula IV and the compound of formula VA react with a closed ring through a side chain, and then deamination protecting group is carried out, thus obtaining the macrolide of formula I. Wherein the amino protecting group is generally removed by acidolysis reaction, wherein the reaction temperature is 20-50 ℃, and the reaction time is about 0.5-10 h. The acid of the acidolysis reaction is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid; the method for implementing the deamination protecting group of the present application may be other methods that can be easily accomplished by those skilled in the art, and is not limited thereto.

And when Cp is nitro, carrying out side chain-to-ring reaction on the compound shown in the formula IV and the compound shown in the formula VA, and carrying out catalytic hydrogenation to reduce the nitro into amino to obtain the macrolide shown in the formula I. Wherein the molar ratio of the compound of formula IV to the compound of formula VA is 1: 1-3. Preferably 1: 1-2. The catalyst for catalytic hydrogenation is selected from palladium carbon or Raney nickel, preferably palladium carbon, the dosage of the catalyst is 10 wt% of the compound shown in the formula IV, and the hydrogenation pressure is normal pressure to 10Mpa, preferably normal pressure; the reaction solvent is selected from alcohols, esters or ethers, preferably alcohols, wherein the alcohol solvent is selected from methanol, ethanol or isopropanol, preferably methanol, the ester solvent is selected from ethyl acetate or isopropyl acetate, preferably ethyl acetate, and the ether solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran or 2-methyl tetrahydrofuran, preferably tetrahydrofuran. The reaction temperature is 20-80 ℃, and the reaction time is 1-10 h. The reduction of nitro group in the present application may be carried out by other methods for reducing nitro group, which can be easily accomplished by those skilled in the art, and is not limited thereto.

Alternatively, the compound of formula IV may be reacted with a compound of formula VB to form an oxazole ring intermediate followed by a ring closure reaction with an alkyne compound (e.g., 3-aminophenylacetylene) to obtain the macrolide of formula I.

Wherein R is₂Is an azido group, A, B is as defined above.

The reaction of the pair of ring closures can be carried out in an organic solvent selected from tetrahydrofuran, acetonitrile, N-dimethylaminobormamide, dimethyl sulfoxide, dichloromethane, toluene, preferably acetonitrile.

The pair of ring closure reactions can also be carried out in a mixed system of the organic solvent and water, and the volume ratio of the organic solvent to the water is 1-10: 1, preferably 2: 1; preferably, the mixed system is an acetonitrile/water mixed system, and the volume ratio of the acetonitrile/water mixed system to the water mixed system is 1-10: 1, preferably 2: 1.

The reaction time of the pair of the closed rings is 0.5-16 h, preferably 2-8 h; the reaction temperature is 50-100 ℃, preferably 50-80 ℃.

The ring-closing reaction may be carried out under the promotion of an organic base selected from one or more of 1, 8-diazabicycloundecen-7-ene (DBU), Dicyclohexylcarbodiimide (DCC), N-dimethylpyridine amine (DMAP), triethylenediamine (DABCO) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN), preferably DBU.

Compounds of formula III are available in accordance with the prior art, including, for example and without limitation: halogenating the compound shown in the formula II to generate a compound shown in the formula III, wherein the reaction formula is as follows:

wherein R, X, Y, W is as defined above.

The halogenation reaction includes, but is not limited to, a fluorination reaction using a fluorinating agent selected from the group consisting of: n-fluorobisbenzenesulfonamide, N-fluoro-benzenedisulfonamide or 1-fluoro-4-hydroxy-1, 4-diazabicyclo [2,2,2] octane bistetrahydroborate, preferably N-fluorobisbenzenesulfonamide. The molar ratio of the fluoro reagent to the compound of formula II is 1: 1-2, preferably 1: 1.2-1.5. The fluorination reaction is carried out at the temperature of-78-30 ℃, preferably-20-0 ℃; the reaction time is 0.5-4 h, preferably 2-3 h.

The organic solvent used in the fluorination reaction is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, 1, 4-dioxane, N-dimethylformamide, ethyl acetate or isopropyl acetate, and a mixed system of N, N-dimethylformamide and tetrahydrofuran is preferred.

The fluorination reaction is preferably carried out under basic conditions, for example in the presence of one or more basic substances selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydrogen or sodium bis (trimethylsilyl) amide (NaHMDS), 1, 8-diazabicycloundecen-7-ene (DBU), preferably potassium tert-butoxide.

The compounds of formula II of the above reaction are available in accordance with the prior art, including for example but not limited to: the compound of formula II is formed by using clarithromycin as a starting material and under the action of Carbonyl Diimidazole (CDI) after sugar hydroxyl group protection. The synthetic route is as follows:

wherein R, X, Y is as defined above. When W ═ H, the compound of formula II is the compound of formula III, however, for convenience, the compound of formula II is still represented in the present invention.

In one embodiment of the present invention, the synthesis of the compound of formula I optionally further comprises desugaring and oxidation reactions. The desugaring and oxidation reaction means that monosaccharide units in intermediate molecules are removed under acidic conditions, and then oxidation reaction is carried out by pyridinium chlorochromate (PCC) or Stevens oxidation to oxidize hydroxyl groups on macrolides into carbonyl groups. The desugarization and oxidation reaction can be carried out at the beginning of the reaction, for example, after the hydroxyl group of the clarithromycin sugar is protected, and after desugarization and oxidation, the compound of formula II is formed under the action of Carbonyl Diimidazole (CDI). Alternatively, the desugarization and oxidation reactions may also be carried out in the middle or late stages of the reaction, for example after synthesis of the compound of formula II, or after synthesis of the compound of formula III, or after synthesis of the compound of formula IV, for example including but not limited to the following reaction schemes:

the compound is further subjected to desugarization, oxidation and fluorination to generate the formula IA solithromycin.

Furthermore, the halo (fluoro) reaction is not limited to be performed before the desugared hydroxyl group protection reaction, optionally, before, after, or between the desugared hydroxyl group protection reaction or the side chain-to-ring closure reaction, as long as the technical solution of the present invention can be achieved to obtain the target compound of formula I (in particular, formula IA solithromycin).

The invention synthesizes the macrolide (especially the solithromycin IA) in the formula I by removing the hydroxyl protecting group firstly and then connecting a ring, and avoids impurities which are difficult to purify and remove generated in the last step of removing the hydroxyl protecting group in the prior art. The target product macrolide I (especially solithromycin IA) obtained by the method has higher purity, better yield, less side reaction, convenient post-treatment and safe operation, and is suitable for large-scale production.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Further, it should be understood that various changes and modifications may be made by one skilled in the art after reading the concept of the present invention and these equivalents are also within the scope of the invention as defined by the appended claims.

Each test method in examples can be carried out according to a conventional method except for the specific conditions noted.

The addition amounts, contents and concentrations of various substances are referred to herein, wherein the percentages indicated refer to mass percentages unless otherwise indicated.

In the examples herein, if no specific description is made about the reaction temperature or the operation temperature, the temperature is usually room temperature (20 to 25 ℃).

For the sake of brevity, the compound of formula II is sometimes referred to herein as "compound II", "compound of formula II", "intermediate of formula II", or "intermediate II", all referring to the compound numbered II, wherein II refers to a compound number/code, such as I, II, III, IV, V, VI, a, B, C, D, etc. Similarly, a macrolide is sometimes referred to herein as macrolide I, or a macrolide of formula I, all of which have the same meaning.

Unless otherwise indicated, the term "aryl", alone or in combination with other groups, refers to an optionally substituted or unsubstituted aromatic ring system. The term aryl includes monocyclic aromatic rings and polycyclic aromatic rings. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and anthracenyl ring systems.

Unless otherwise indicated, the term "heteroaryl", alone or in combination with other groups, refers to an aromatic ring system containing one or more heteroatoms, such as oxygen, nitrogen, sulfur, selenium, and phosphorus. The term heteroaryl may include 5-or 6-membered heterocycles, polycyclic heteroaryl ring systems and polyheterocyclic ring systems.

As used herein, the term "aralkyl" is equivalent to the term arylalkyl, and represents one or more substituted or unsubstituted monocyclic or polycyclic aromatic rings attached to an alkyl moiety; illustrative examples include, but are not limited to, benzyl, diphenylmethyl, trityl, 2-phenylethyl, 1-phenylethyl, 2-pyridylmethyl, 4' -dimethoxytrityl, and the like.

Unless otherwise indicated, the term "saccharide" includes monosaccharides, disaccharides and polysaccharides which may be optionally substituted or unsubstituted, for example including saccharides and deoxy saccharides which may be optionally substituted with amino, amido, ureyl, halogen, nitrile or azido groups. Illustrative examples include glucosamine, N-acetylglucosamine, desosamine, forosamine, sialic acid, and the like.

Unless otherwise indicated, the term "alkyl" refers to straight, branched and/or cyclic ("cycloalkyl") hydrocarbon groups having 1 to 20 (e.g., 1 to 10, preferably 1 to 4) carbon atoms, wherein the alkyl moiety having 1 to 4 carbons is referred to as "lower alkyl". Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylphenyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moieties can be monocyclic or polycyclic and include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Other examples of alkyl moieties include alkyl groups having branched, and/or cyclic moieties, such as 1-ethyl-4-methyl-cyclohexyl. Furthermore, the term "alkyl" includes saturated hydrocarbon groups as well as alkenyl and alkynyl moieties.

Example 1 preparation of a compound of formula III-1 (R ═ AcO)

2.05g of the acetyl protected compound of formula II-1 (2.90mmol) are dissolved in 20ml of a DMF/THF mixture (9:1), 0.39g of potassium tert-butoxide (3.48mmol) are added portionwise at-20 ℃ and after completion the mixture is stirred for 0.5h at-20 ℃ and then 1.01g of NFSI (N-fluorobisbenzenesulfonamide) (3.19mmol) are added and the reaction is continued for two h at-20 ℃. After the reaction was completed by sampling and HPLC detection, a small amount of water was added to quench the reaction, and the reaction solution was diluted with 50ml of ethyl acetate, then washed with saturated brine several times (50 ml/time), dried over anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product (which was used directly in the next step). The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao yellow sea) using 4L ethyl acetate as eluent to give 1.57g of a foamy white solid III-1 (yield 74.7%).

ESI(M+1)＝724

EXAMPLE 2 preparation of the Compound of formula IV-1

7.23g of Compound III-1(0.01mol) were dissolved in 100ml of methanol and stirred at room temperature overnight. After sampling and detecting the reaction, the solvent of the reaction solution was distilled off to obtain 7g of a white solid, and the crude product was used in the next step. The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao yellow sea), 4L dichloromethane: methanol 30:1 and 1% triethylamine as eluent to give 5.78g of a foamy white solid IV-1 (yield 85%).

ESI(M+1)＝682。

Example 3 preparation of solithromycin of formula IA (Cp ═ NH)₂)

6.82g of the compound of formula IV-1 (0.01mol) and 6.93g of the compound of formula VA-1 (0.03mol) were mixed in 100ml of acetonitrile (water: 9:1), and the mixture was heated under reflux overnight. After sampling and detection of complete reaction, heating is stopped, after the reaction liquid is cooled to room temperature, the organic solvent is distilled off, 50ml of water is added for dilution, 20ml of dichloromethane is used for extraction, organic phases are combined, anhydrous sodium sulfate is dried, suction filtration and spin drying are carried out, column chromatography purification is carried out, (silica gel 200 plus 300 meshes, Qingdao yellow sea), 4L of dichloromethane, methanol, 30:1 and 1% of triethylamine are used as eluent, and 6.34g of foamy white solid, namely solithromycin IA (yield 75%) is obtained.

ESI(M+1)/2＝423。

EXAMPLE 4 preparation of a Compound of formula III-2 (R ═ BzO)

The compound of formula II-2 (3.84g, 0.005mol) was dissolved in DMF (20ml), replaced with nitrogen, and the reaction was cooled to-25 ℃. Potassium tert-butoxide (0.84g, 0.0075mol, 1.5eq) was added and after completion, the reaction was carried out at-20-25 ℃ for 1 h. NFSI (2.5g, 0.0075mol, 1.5eq) was added in portions, and after completion, the reaction was carried out at-20 to-25 ℃ for 1 h. Sampling and detecting that the raw materials completely react, dropwise adding 60ml of ice water, controlling the temperature to be not more than 10 ℃, and separating out solids. After the dropwise addition, stirring for 15min, carrying out suction filtration, and leaching with ice water. The filter cake was dissolved in 50ml of ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, spin-drying and purification by column chromatography gave 3.14g of white solid III-2 (yield 80%).

MS＝786。

EXAMPLE 5 preparation of the Compound of formula IV-1

7.86g of the compound of the formula III-2 (0.01mol) was dissolved in 100ml of methanol and stirred at room temperature overnight. After sampling and detecting the reaction, the solvent of the reaction solution was distilled off to obtain 7g of a white solid, and the crude product was used in the next step. The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao yellow sea), 4L dichloromethane: methanol 30:1 and 1% triethylamine as eluent to give 5.44 g foamy white solid IV-1 (yield 80%).

ESI(M+1)＝682。

Example 6 preparation of solithromycin of formula IA (Cp ═ amino protecting group-NHBoc)

Compound IV-1(3.4g, 0.005mol), Boc protected amino side chain VA-2(4.96g,0.015mol, 3eq), acetonitrile (20ml), and water (2ml) were mixed and reacted under nitrogen at 55-60 ℃ for 6 h. Sampling, detecting the reaction, spinning dry the reaction liquid, and purifying by column chromatography. (silica gel 200-300 mesh, Qingdao yellow sea), 4L of dichloromethane: methanol-30: 1 and 1% triethylamine as eluent, 3.3g of foamy white solid, i.e. the compound VI-1, was obtained in 70% yield.

3.3g of the VI-1 compound solid is dissolved in 50ml of dichloromethane DCM, trifluoroacetic acid (1.14g, 0.01mol, 3eq) is added, and the mixture is stirred and reacted at 20-25 ℃ for 4 h. And (3) spin-drying the reaction solution, adding water for dilution, adjusting the pH to 8-9, extracting with DCM (30 ml. times.3), combining organic phases, drying with anhydrous sodium sulfate, performing suction filtration, spin-drying, and purifying by column chromatography to obtain 1.97g of IA solimycin white solid with the yield of 70%.

MS＝423[(M+2)/2]。

Example 7 preparation of solithromycin of formula IA (Cp ═ NH)₂)

Compound IV-1(6.81g, 0.01mol), azidobutylamine (2.28g, 0.02mol, 2eq), acetonitrile and water were charged into a reaction flask and reacted at 55 to 65 ℃ overnight. After the reaction of compound IV-1 was completed by sampling and checking, the solvent was distilled off under reduced pressure, the residue was diluted with water (50ml), extracted with ethyl acetate (50 ml. times.2), the organic phases were combined, washed with saturated brine (30ml), dried over anhydrous sodium sulfate, filtered by suction, dried by spinning, and purified by column chromatography to obtain 5.46g of a white solid, i.e., the compound of formula VI-2, in 75% yield and MS (M +1) ═ 728.

The intermediate VI-2(6.4g, 0.0088mol) was charged into a reaction flask, dissolved in 30ml of ethyl acetate, added with m-aminophenylacetylene (1.24g, 0.0106mol, 1.2eq), water 30ml, sodium ascorbate (0.87g, 0.0044mol, 0.5eq), stirred to dissolve clear, and added dropwise with an aqueous solution of copper sulfate (copper sulfate pentahydrate, 0.44g, 0.00176mol, 0.2eq, 25ml of water). After dropping, the mixture was stirred at room temperature overnight. After sampling and detecting that the intermediate IV-2 completely reacts, filtering the reaction liquid through diatomite, separating filtrate, extracting water phase ethyl acetate (30ml x 2), combining organic phases, drying through anhydrous sodium sulfate, filtering, spin-drying, purifying by column chromatography (silica gel 200-300 meshes, Qingdao yellow sea), and using 4L dichloromethane, methanol 30:1 and 1% triethylamine as eluent, 5.2 g foamy white solid, namely the solithromycin IA is obtained (yield 70%).

ESI(M+1)/2＝423。

Example 8 preparation of solithromycin of formula IA (Cp ═ NO)₂)

Compound IV-1(3.4g, 0.005mol), nitro side chain VA-3(4.96g, 0.015mol, 3eq), acetonitrile (20ml), and water (2ml) were mixed and reacted by heating at 55-60 ℃ for 6 hours under nitrogen protection. Sampling to detect the reaction completion, spin-drying the reaction solution, and purifying by column chromatography (silica gel 200-300 mesh, Qingdao yellow sea) with 4L dichloromethane: methanol-30: 1 and 1% triethylamine as eluent to obtain 2.62g foamy white solid, i.e. the compound of formula VI-3, with a yield of 60%.

Dissolving 2.62g of the compound of formula VI-3 in 100ml of THF, adding 10% palladium on carbon (200mg), replacing with hydrogen, and stirring at 20-25 ℃ for 6 h. Sampling and detecting that the reaction is complete, filtering out palladium carbon, spin-drying reaction liquid, and recrystallizing a crude product with methanol to obtain 1.26g of IA solimycin white solid.

MS＝423[(M+1)/2]。

EXAMPLE 9 preparation of the Compound of formula IV-2

7g of Compound II-1(0.01mol) was dissolved in 50ml of methanol and stirred at room temperature overnight. After sampling and detecting the reaction, the solvent of the reaction solution was evaporated off, and the crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao yellow sea), 4L dichloromethane: methanol-30: 1 and 1% triethylamine as eluent, to obtain 4.77g of a foamy white solid, i.e., formula IV-2 (yield 72%).

ESI(M+1)＝664。

EXAMPLE 10 preparation of the Compound of formula IV-1

6.6g of the compound of the formula IV-2 (0.01mmol) are dissolved in 20ml of a DMF/THF mixture (9:1), 1.34g of potassium tert-butoxide (0.012mmol) are added portionwise at-20 ℃ and, after completion, the mixture is stirred for 0.5h at-20 ℃. Then, a mixture of 3.47g of NFSI (0.011mmol) in 20ml of DMF was added dropwise, and the reaction was continued at-20 ℃ for two hours. After the reaction was detected by HPLC, a small amount of water was added to quench the reaction, and the reaction solution was diluted with 50ml of ethyl acetate, washed with saturated brine several times (50 ml/time), dried over anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product (which was used directly in the next step). The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao yellow sea), 4L dichloromethane: methanol 30:1 as eluent, 4.56g of a foamy white solid IV-1 (yield 67%) were obtained.

LC-MS M+1＝664。

EXAMPLE 11 preparation of solithromycin of formula IA

6.63g of the compound of formula IV-2 (0.01mol) and 6.93g of the compound of formula VA-1 (0.03mol) were mixed with 100ml of acetonitrile (water: 9:1), and the mixture was heated under reflux overnight. After sampling and detection of complete reaction, heating is stopped, after the reaction liquid is cooled to room temperature, the organic solvent is evaporated, 50ml of water is added for dilution, 20ml of dichloromethane is used for extraction, organic phases are combined, anhydrous sodium sulfate is dried, suction filtration and spin drying are carried out, column chromatography purification (silica gel 200-mesh 300-mesh, Qingdao yellow sea) is carried out, 4L of dichloromethane, methanol and 1% triethylamine are used as eluent, and 5.78g of foamy white solid is obtained (yield is 70%). LC-MS (M +1)/2 ═ 414.

5.78g of the foamy white solid obtained above (0.007mmol) are dissolved in 20ml of DMF solution and, after addition of 0.94g of potassium tert-butoxide (0.0084mmol) at-20 ℃ and completion, the mixture is stirred for 1 hour at-20 ℃. Then a mixture of 2.65g NFSI (0.0084mmol) in 20ml DMF was added dropwise, the temperature was controlled at less than-20 ℃. After the addition, the reaction was continued at-20 ℃ for two hours. After the reaction was detected by HPLC, a small amount of water was added to quench the reaction, and the reaction solution was diluted with 50ml of ethyl acetate, washed with saturated brine several times (50 ml/time), dried over anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product (which was used directly in the next step). The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao yellow sea) with 4L dichloromethane: methanol 30:1 as eluent to give 4.26g of a foamy white solid, solithromycin IA (yield 72%).

ESI(M+1)/2＝423。

Claims

1. A process for the preparation of a macrolide, comprising the steps of: firstly, removing a sugar hydroxyl protecting group from a compound shown in a formula III to obtain a compound shown in a formula IV, and then carrying out side chain to joint ring reaction to obtain a macrolide shown in a formula I; the reaction formula is as follows:

wherein R is an acyl protecting group;

x, Y together with the attached carbon form carbonyl-C ═ O;

w is H, halogen;

A. b together form- (CH)₂)₄C is aminophenyl; removing a sugar hydroxyl protecting group from the compound of the formula III in an alcohol solvent at room temperature to obtain a compound of a formula IV; the alcohol solvent is selected from one of methanol, ethanol, isopropanol, n-propanol or n-butanol;

the side chain to switch ring step is carried out in a mixed system of acetonitrile and water, the reaction time of the side chain to switch ring is 0.5 h-16 h, and the reaction temperature is 50-100 ℃.

2. The method of claim 1, wherein R is benzoyl or acetyl; w is F.

3. The process according to claim 1, wherein the compound of formula IV is coupled with the compound of formula VA via a side chain to a ring to obtain the macrolide of formula I,

wherein CP is amino or nitro protected with an amino protecting group, A, B is as described in claim 1;

when CP is amino protected by amino protecting group, the compound of formula IV and the compound of formula VA are subjected to ring closing by side chain pair, and then deamination protecting group is carried out to obtain the macrolide of formula I; or

And when the CP is nitro, carrying out catalytic hydrogenation on the compound of the formula IV and the compound of the formula VA to reduce the nitro into amino after side chain butt joint and ring closure, thus obtaining the macrolide of the formula I.

4. A process according to any one of claims 1 to 3, wherein the volume ratio of acetonitrile to water is from 1 to 10: 1.

5. The method according to any one of claims 1 to 3, wherein the side chain is reacted with the linker ring for 2 to 8 hours at a temperature of 50 to 80 ℃.

6. The method of claim 1, optionally further comprising a fluorination reaction, said fluorination reaction being carried out before, after, or between the desugared hydroxyl protection reaction or side chain reaction to a linker ring.

7. The method according to claim 6, wherein the fluorination reaction uses a fluorinating agent selected from the group consisting of N-fluorobisbenzenesulfonamide, N-fluoro-benzenedisulfonamide, and 1-fluoro-4-hydroxy-1, 4-diazabicyclo [2,2,2] octane bistetrahydroborate.

8. The method according to claim 6, wherein the organic solvent used in the fluorination reaction is selected from a mixed system of N, N-dimethylformamide and tetrahydrofuran.

9. The method according to claim 6, wherein the fluorination reaction is carried out under basic conditions in the presence of one or more basic substances selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, NaHMDS or DBU.

10. The method according to claim 6, wherein the fluorination reaction is carried out at a temperature of-78 ℃ to 30 ℃ for a reaction time of 0.5h to 4 h.