CN109748929A - A kind of preparation method of compound - Google Patents

Abstract

Invention is related to the preparation method of pharmaceuticals intermediate boronic acid derivatives.The present invention provides a kind of new synthetic schemes of boronic acid compounds, with technical solution of the present invention, reaction is clean, high income, by simple crystallization protocol can high yield high-quality obtain target product.

Description

A kind of preparation method of compound

Technical field

Invention is related to the preparation method of pharmaceuticals intermediate boronic acid derivatives.

Background technique

Acalabrutinib(ACP-196, trade name Calquence) it is by AstraZeneca (AstraZeneca) pharmacy public affairs Second generation Bruton tyrosine kinase (BTK) covalency inhibitor for taking charge of research and development has the characteristics that potent, selectivity is high. Acalabrutinib can promote the lasting high response rate of chronic lymphatic leukemia (CLL) patient's body, pass through blocking BTK can inhibit the growth signals of CLL cell, until promoting cancer cell death, have very high specificity to its target.Make For therapeutic agent of new generation, Acalabrutinib is a kind of more selective irreversible BTK inhibitor, will not destroy it His molecular channel important to blood platelet and immune function can preferably improve the safety and effectively of generation BTK inhibitor Property.

Because of its unique curative effect, Acalabrutinib is successively by Food and Drug Adminstration of the US (FDA) and European drug pipe Reason office (EMA) authorizes treatment lymphoma mantle cell, chronic lymphocytic leukemia/small lymphocyte lymthoma/jacket cell lymph The Orphan drug status of tumor and lymhoplasmacytoid lymphoma.U.S. FDA in November, 2017 announces approval AstraZeneca Acalabrutinib suffers from lymphoma mantle cell (mantle cell lymphoma) for treatment and once received at least one The adult patient of secondary treatment.The Calquence of AstraZeneca research and development is that the treatment of lymphoma mantle cell brings dawn.

Acalabrutinib synthetic method is by the visible patent of route that Merck Sharp & Dohme Corp. announces CN103889987B.An important intermediate is boronic acid compounds 4 in the route.Firstly, compound 4 and bromo compound 5 Under the conditions of microwave reaction, compound 6 is prepared by the coupling reaction that Pd is catalyzed, compound 6 is molten by bromination acetate hydrogen Liquid goes Cbz radical protection to obtain compound 7, and then compound 7 obtains Acalabrutinib through condensation reaction with 2- tetrolic acid. Specific synthetic route is as follows:

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Searching document, only document Bioorganic & Medicinal Chemistry Letters, 2006,16, The synthesis of 5217 pairs of boric acid 4 is reported that synthetic route is as follows, but the yield that do not point the route.

Above-mentioned synthetic schemes needs the raw material 4- Carboxybenzeneboronic acid and condensing agent BOP more expensive using price, is unfavorable for amplifying Production and cost control.

Organometallic reagent is prepared with halides, is then reacted again with borate, is a kind of usual way for preparing boric acid. But searching document, and have no the report for preparing boronic acid compounds 4 for starting material with compound 3.Analyze reason, possible cause To be influenced by substrate amido bond: first is that the presence of amido bond prevents the corresponding Grignard Reagent of compound 3 from often in molecule Rule directly react synthesis with magnesium metal；Even second is that the corresponding organometallic reagent of compound 3 such as lithium reagent or grignard examination The active H that agent also can preferentially capture on intramolecule amide after its formation causes to generate 2-aminopyridine benzamide, leads to nothing Method and borate occur intermolecular reaction and generate compound 4.Therefore routinely experimental program hardly results in desired effect.

There is also certain particularity for the synthesis of literature survey discovery compound 3.Synthesis compound 3 is needed using 2- amino Pyridine, and 2-aminopyridine compound itself has certain particularity, common amido bond synthetic method is used for this amido bond Building effect it is poor.Such as in Tetrahedron Letters 2009,50, in 1986 articles, author explicitly points out " When the acylations are attempted with weakly nucleophilic amines, however, they are often met with long reaction times and harsh conditions. …Although there is ample literature precedent for carboxylic acid couplings with 2- aminopyridines, the yields tend to be quite variable and more often than not, require transformation to the acid chloride prior to coupling.".For compound 3 Synthesis is rarely reported, and the yield of patent WO2015048689 and WO2015104722 report is respectively 65% and 45%.Reaction retrieval The only two examples such as following table of document.

Even benzoic acid often uses the document report of condensation reaction condition also considerably less with compound 2, Journal of Medicinal Chemistry, 2014, 57, 6393 reports are condensing agent using more expensive TBTU, and yield is only 65%, compared with Hardly possible is applied to commercially produce.

Repetition document (1) converts acyl chlorides for compound 1 and reacts prepare compound 3 with compound 2 again, and reaction result is except life Other than target compound 3, has a large amount of two and by-product is replaced to generate.

The generation of one side by-product can consume raw material, cause the decline for reacting yield itself；On the other hand, excessive by-product The presence of object causes compound 3 to isolate and purify difficulty, and the mode of used silicagel column is needed to purify, and yield reported in the literature is silicon Rubber column gel column is isolated.Such case causes a large amount of losses of product with the crystallization purifying that industrial production generallys use, and yield is aobvious Write decline.

Using technical solution of the present invention, prepare compound 3 is reacted completely, and yield is up to 93%, passes through the simply side of crystallization Case can obtain the target compound 3 of high-quality to be up to 84% yield, and technical advantage is obvious.

Summary of the invention

The present invention, provides a kind of synthetic schemes of new boronic acid compounds 4, and synthetic route is as follows.

4- bromobenzoic acid reacts to obtain midbody compound 3 under the action of CDI with 2-aminopyridine first.Compound 3 In the presence of lithium reagent, react to obtain target product compound 4 with borate.It sees and belongs to often on the reaction process surface The reaction of rule property, but there are more technical problems for real reaction process:

(1) as described above, the first step reacts existing document report, amido bond is prepared using traditional condensing agent, due to 2- The special characteristic electron of aminopyridine, the yield of the reaction is very low, and so as to cause less economical, large-scale production is limited System.CDI scheme that the present invention uses can high yield under mild reaction conditions by changing the activity of carboxylic acid substrate Obtain target product.Another scheme using the sulphonic acid chloride being of little use as activating reagent, such as MsCl, separation yield 69%, compared with There is also greater advantages for existing document report.

(2) second step reaction needs first to carry out under organolithium or Grignard Reagent existence condition, and exchange reaction generates corresponding Aryl lithium or Grignard Reagent.Contain amido bond in compound 3, along with the presence of pyridyl group, amido bond-NH hydrogen is former Sub acid very strong, activity is very high, can react first with organolithium reagent or Grignard Reagent.Or the reactive hydrogen being quenched Lithium reagent or Grignard Reagent after closing 3 metal exchange of object, generate compound 3 falls bromine by-product compounds 8.

For example, under cryogenic, mixing Grignard Reagent, target product yield using isopropylmagnesium chloride and butyl lithium 45.8%, Main By product is compound 8.Using only butyl lithium, borate is added dropwise again after being converted to lithium reagent, yield is 50.6%, it is approached with the above-mentioned Grignard Reagent yield that mixes.It attempts using NaH or LiHMDS first by the active hydrogen consumption on amido bond Fall, then add butyl lithium, reaction fails the progress according to anticipation.In addition, we also attempt the reactive hydrogen on amido bond Replaced and protected N atom, does not obtain the target product of corresponding N protecting atom.

It eventually passes through experiment to grope, it has been surprisingly found that changing charging sequence, reaction is greatly improved.Usual feelings Under condition, butyl lithium can be reacted with borate, consume butyl lithium itself and reaction substrate borate, so that reaction is deteriorated, but for this Reaction but gives very unexpected result.Optimal result is as shown in eighth row: under cryogenic, to compound 3 and borate Mixed system in, be added dropwise butyl lithium, product compound 4 can be obtained with high yield.

The starting material that the present invention uses is cheap and easy to get, and reaction condition is mild, solves above-mentioned 2-aminopyridine amido bond Synthesis and synthesis boric acid during fall the serious technical problem of bromine by-product, target product is obtained with very high yield.Entirely Expensive reagent is not used in experimentation, provides a kind of efficient method for the amplification production of boronic acid compounds 4.

Specific embodiment

Presently filed embodiment is described below by embodiment, it will be appreciated by the person skilled in the art that these are specific Embodiment only indicate to achieve the purpose that the application and the implementation technical solution that selects, be not the limit to technical solution System.According to teachings of the present application, be to the improvement of technical scheme in conjunction with the prior art it is obvious, belong to the application guarantor The range of shield.

Implementation condition used in the examples can do further adjustment according to specific requirement, and the implementation condition being not specified is logical It is often the condition in routine experiment.Wherein, the chemical reagent used in the examples below is commercially available chemical reagent.

Embodiment 1

By 2.0 g parabromobenzoic acids (compound 1), 1.11 g triethylamines are added in reaction flask, and 16 mL dioxane are added, to System be added dropwise 1.25 g of methylsufonyl chloride, be warming up to 40 °C of 2 h of stirring, to system be added 1.35 g 4-dimethylaminopyridine with 1.41 g o-aminopyridines add 60 °C of system 3 h of reaction, the water quenching reaction of 20 mL, the ethyl acetate extraction two of 20 mL It is secondary, merge organic phase, is spin-dried for solvent, normal heptane/ethyl acetate column chromatographic purifying obtains product, yield 69%.

3 nuclear magnetic data of compound is as follows:

¹H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.40 (dd, J = 4.8, 1.1 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.03 – 7.93 (m, 2H), 7.91 – 7.81 (m, 1H), 7.77 – 7.67 (m, 2H), 7.26 – 7.11 (m, 1H).

Embodiment 2

By 20.0 g parabromobenzoic acids (compound 1), 19.34 g N, N- carbonyl dimidazoles are added in reaction flask, and 200 mL are added Toluene, 60 °C of system 2 h of stirring.14.04 g o-aminopyridines are added, add 100 °C of system 4 h of reaction.Saturated sodium carbonate It washed once, pure water washes twice, and saturated salt solution washed once, and obtains organic phase and is concentrated into 100 mL, is cooled to 0 ~ 5 ° C stirs 1 h, filters, and drying obtains product, is white solid, yield 84%.

Embodiment 3

The tetrahydrofuran solution of the isopropylmagnesium chloride of 10 mL, 2 mol/L is added in reaction flask, 20 mL tetrahydro furans are added It mutters, system is cooled to -20 ~ -30 °C, and the hexane solution of the n-BuLi of 16.4 mL, 2.5 mol/L, stirring 10 is added dropwise min.The tetrahydrofuran solution of 35 mL compounds 3 is added dropwise in Nei Wen -20 ~ -30 °C of control, stirs 20 min.Control Nei Wen -20 ~ -30 °C, 3.75 g trimethylborates are added dropwise, system maintains -20 ~ -30 °C of 16 h of reaction, pours into 50 mL saturated ammonium chlorides and quench It going out, 100 mL ethyl acetate extract three times, merge organic phase, are spin-dried for solvent, and methylene chloride/methanol column chromatographic purifying obtains product, Yield 45.8%.

4 nuclear magnetic data of compound is as follows:

¹H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.52 – 8.36 (m, 1H), 8.35 – 8.17 (m, 2H), 8.11 – 7.79 (m, 5H), 7.24 – 7.12 (m, 1H).

Embodiment 4

1.98 g compounds 3 are added into reaction flask, 20mL tetrahydrofuran is added, system is cooled to -60 ~ -70 °C, under low temperature The hexane solution of the n-BuLi of 6.8 mL, 2.5 mol/L is added, 2.72 g triisopropyl borate esters are added.Reaction terminates, Reaction solution pours into 100 mL saturated ammonium chlorides and is quenched, and 200 mL ethyl acetate are extracted twice, and merges organic phase, uses saturated common salt Water washing, rotation remove solvent, with ethyl acetate and normal heptane mashing purifying, obtain product, yield 53%.

Embodiment 5

10 mL tetrahydrofurans and 1.01g compound 3 are added into reaction flask, system is cooled to -60 ~ -70 °C, is added 1.36 G triisopropyl borate ester.The hexane solution of the n-BuLi of 6 mL, 2.5 mol/L is added under low temperature, 1 mL boric acid is added in centre Three isopropyl esters.Reaction terminates, and reaction solution is poured into 50 mL saturated ammonium chlorides and is quenched, and 100 mL ethyl acetate are extracted twice, and merges Organic phase is washed with saturated common salt, and rotation removes solvent, with ethyl acetate and normal heptane mashing purifying, obtains product, yield 86%.

Embodiment 6

500 mL tetrahydrofurans and 50 g compounds 3 are added into reaction flask, system is cooled to -60 ~ -70 °C, and 84.9g is added Triisopropyl borate ester.The hexane solution of the n-BuLi of 378 mL, 2.5 mol/L is added under low temperature, reaction terminates, and will react Liquid pours into 10% ammonium chloride solution of 500mL and is quenched, and 500 mL ethyl acetate are extracted twice, and merges organic phase, uses saturated salt solution It washes, rotation removes solvent, with isopropyl acetate and normal heptane mashing purifying, obtains product, yield 90%.

The application includes but is not limited to above embodiments, all any equivalent substitutes carried out under the principle of the application spirit or Local improvement all will be regarded as within the scope of protection of this application.

Claims (8)

1. a kind of method of prepare compound 4 comprising the steps of:

Compound 3 is reacted with borate under alkaline condition generates compound 4,

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2. according to claim 1, R1 is the alkyl of C1 ~ C10, aryl or substituted aryl；Preferably, R1 is methyl, different Propyl, phenyl；It is furthermore preferred that R1 is isopropyl.

3. according to the method described in claim 1, compound 3 can react to obtain compound 4 under alkaline condition with borate, Wherein the method includes -78 °C to 50 °C at a temperature of, in organic solvent, compound 3 reacts preparation with borate Formula compound 4, wherein alkali can be organolithium reagent and Grignard Reagent, butyl lithium, ethyl-lithium, amyl lithium, phenyl lithium, methyl Lithium, cyclohexyl lithium, isopropylmagnesium chloride, isopropyl magnesium bromide etc. are one such or a variety of；Preferably, the alkali is butyl Lithium；It is highly preferred that the alkali is n-BuLi.

4. a kind of method of prepare compound 3 comprising the steps of:

Compound 1 generates compound 3 with chemical combination 2 under the action of CDI,

。

5. according to the method described in claim 4, wherein the method includes -78 °C to 150 °C at a temperature of, organic In solvent, compound 1 reacts prepare compound 3 with compound 3, and the organic solvent is selected from DMF, DMA, acetonitrile, tetrahydrofuran, Methyltetrahydrofuran, toluene, dimethylbenzene, dioxane, dimethyl sulfoxide, N-Methyl pyrrolidone, sulfolane, in DCM equal solvent One or more；Preferred solvent is THF and toluene.

6. according to the method described in claim 4, the impurity level in its reaction system 5% hereinafter, more preferably, impurity level Below 2%.

7. a kind of method of prepare compound 3 comprising the steps of:

Compound 1 is under the action of MsCl, TsCl, NsCl and chemical combination 2 generates compound 3,

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8. according to the method described in claim 7, wherein the method includes -78 °C to 150 °C at a temperature of, organic In solvent, compound 1 reacts prepare compound 3 with compound 3, and the organic solvent is selected from DMF, DMA, acetonitrile, tetrahydrofuran, Solvent in methyltetrahydrofuran, toluene, dimethylbenzene, dioxane, dimethyl sulfoxide, N-Methyl pyrrolidone, sulfolane, DCM etc. It is one or more of；Preferred solvent is dioxane.