CN105777681A - Preparation methods of himbacine analogue and intermediate thereof - Google Patents
Preparation methods of himbacine analogue and intermediate thereof Download PDFInfo
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- CN105777681A CN105777681A CN201410777961.3A CN201410777961A CN105777681A CN 105777681 A CN105777681 A CN 105777681A CN 201410777961 A CN201410777961 A CN 201410777961A CN 105777681 A CN105777681 A CN 105777681A
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/55—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
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Abstract
The invention provides preparation methods of a himbacine analogue and intermediates thereof. The invention specifically provides novel preparation methods of a compound A, a compound 4, a compound D and a compound C. According to the invention, a scheme for preparing the compound A does not require a process for reducing carboxylic acid into aldehyde, but directly oxidizing corresponding alcohol into corresponding aldehyde. The operation is safe. In prior arts, carboxylic acid is first converted into acyl chloride, and acyl chloride is catalytically hydrogenated into aldehyde with a palladium catalyst. In the above process, anhydrous palladium-carbon is needed. With the methods provided by the invention, the above harsh condition is avoided. The preparation methods are simple, and operation steps are easy. Especially, when a hydroxyl group protection group P is benzyl group, nitro group can be reduced into amino group when the protection group P is removed. Therefore, the reaction steps are greatly simplified, and raw materials and agents are saved. The entire route has the advantages of low production cost and high yield, and is suitable for industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry art, the preparation method being specifically related to himbacine (himbacine) analog and intermediate thereof..
Background technology
Authorization Notice No. is that CN1659162B(is incorporated in the present invention by reference of text) patent disclosure there is the himbacine analogs of Thrombin receptor antagonist effect, structure is such as shown in following formula: compound C:
,
Compound C has treatment thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, impatiently choke plug, glomerulonephritis, tbrombotic stroke, peripheral vascular disorder, cerebral ischemia, cancer etc. act on (referring to WO03089428).On 05 08th, 2014, FDA ratified the sulfate listing of compound C, is mainly used in the patient and the artery of lower extremity Patients with Embolization that there are heart disease history of attack.
Following formula: compound A is the key intermediate preparing compound C:
。
The preparation method that WO2006076415 and WO2008005348 discloses compound A, as shown in method 1 and method 2:
Method 1.
Method 2.
Namely WO2006076564 discloses compound A(shown in following method 3, following formula: compound 6) preparation method:
Method 3.
WO2006076452 is come into the open three kinds of preparation methoies of compound A, method 4 ~ 6 specific as follows:
Method 4.
Method 5.
Method 6.
The preparation method of the compound A disclosed in said method 1 ~ 6, is all adopt Ester hydrolysis to become carboxylic acid, carboxylic acid to restore into aldehyde to obtain；Or become carboxylic acid or carboxylate by amide hydrolysis, then be reduced into the aldehyde of correspondence by carboxylic acid or carboxylate and obtain.Said method all has the disadvantage in that reaction scheme is long, total recovery is low, severe reaction conditions, particularly to obtain acid through superamide or Ester hydrolysis, carboxylic acid prepare the course of reaction of aldehyde, relate to first being prepared into acyl chlorides by carboxylic acid, acyl chlorides obtains aldehyde then through palladium charcoal catalytic hydrogenation, and yield is low, poor operability, and especially palladium charcoal catalytic hydrogenation to use anhydrous palladium charcoal, during use, danger is higher, is not suitable for industrialized production.
Summary of the invention
For overcoming the defect of prior art, the invention provides and a kind of new prepare compound A and the method preparing compound C.
A kind of preparation method of compound A,
,
Described compound A is through peroxidization by compound 1, changes into,
,
Wherein, R1It is the alkyl with 1 to 4 carbon atom, such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, 2-methyl tertbutyl；Preferably, R1For ethyl.
The described reaction dissolvent being prepared compound A through peroxidization by compound 1 is selected from dichloromethane (DMC), isopropanol, dimethylformamide (DMF) or dimethyl sulfoxide (DMSO)；Oxidant used includes manganese dioxide, Pyridinium chlorochromate on silica gel (PCC), Dess-Matin reagent or Swerm oxidising agent, it is preferred that described reaction dissolvent is DCM, described oxidant is Swerm oxidising agent (such as oxalyl chloride-DMSO, trifluoroacetic anhydride-DMSO).
Further, in said method, described compound 1 is to be reacted with alkyl halo-formiates by compound 2, changes into:
,
Wherein, described alkyl halo-formiates be preferably bromo-, chloro-or iodo-Arrcostab；Wherein moieties and the R in compound 1 in Arrcostab1Identical；Illustrate, the R in compound 11When being preferably ethyl, described alkyl halo-formiates is preferably halogen formate ethyl ester, more preferably chloro ethyl formate；Described reaction dissolvent is selected from oxolane (THF), toluene, dichloromethane, acetonitrile or ethyl acetate, it is preferable that described reaction dissolvent oxolane, temperature is 0 DEG C ~ RT.
Further, in said method, described compound 2 is by compound 3, changes into:
,
Wherein, P is hydroxyl protecting group；
Preferably, described hydroxyl protecting group P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, substituted or unsubstituted C1~6Alkyl, benzyl, the benzyl replaced by one or more substituent groups, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro；Further preferred, hydroxyl protecting group P is trimethyl silicon based, and triethyl group is silica-based; t-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, formoxyl; acetyl group, benzoyl, chloromethyl acetyl group; methyl, ethyl, propyl group; the tert-butyl group, ethoxyethyl group, benzyl; trityl or to methoxy-benzyl, it is most preferred that P is benzyl；
Described changed into the reaction of compound 2 by compound 3 and can first the protection base P in compound 3 be sloughed, then again the nitroreduction sloughing the compound 3 of protection base P is become amino；Single step reaction can also be passed through, protection base P is sloughed and nitroreduction is become amino simultaneously；Preferably, by the solvent sloughed of the protection base P in compound 3 selected from THF, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene, ethanol, water, or ethanol water；The described reaction condition sloughing hydroxyl protecting group can according to this area conventional slough hydroxyl protecting group operation.Illustrate, when hydroxyl becomes alkyl ether with protection base p-shaped, it is common to use Lewis acid treatment, slough moieties, for instance when P is methyl or the tert-butyl group, Lewis process, demethylating or the tert-butyl group can be adopted, as adopted BF3-ether is demethylating under cryogenic；When P is trityl group, hydrogenation reaction or lithium metal can be adopted to process, slough；When (namely hydroxyl becomes the benzyl oxide of benzyl oxide or substituent group with protection base p-shaped; when P is benzyl; the benzyl replaced by one or more substituent groups) time; generally adopt hydrogenation reaction or lithium metallic reducing; the benzyl making benzyl or replacement removes; described reaction is preferably in, under palladium catalyst catalytic condition, being undertaken by hydro-reduction, and reaction pressure is 3 ~ 6atm；Described palladium catalyst can be palladium charcoal, palladium dydroxide charcoal, in another embodiment, it is preferable that reaction dissolvent is THF, and catalyst is Pd(OH)2/ C, glacial acetic acid, reaction pressure is 3 ~ 4atm, and reaction temperature is 50 DEG C ~ 120 DEG C；When P is substituted or unsubstituted C1~6Silylation is (as trimethyl silicon based; triethyl group is silica-based; t-Butyldimethylsilyl; tert-butyl diphenyl is silica-based) tetraalkyl amine fluoride (such as TBAF) elimination can be passed through; or adopt HCl-MeOH, HCl-dioxane, or AcOH-THF system removes silicon-based protecting group; owing to Si-F bond is made a concerted effort bond energy more than Si-O, it is possible to adopt fluorion F-to slough silicon-based protecting group；When P is alkoxyalkyl (such as alkoxy methyl), can remove under strongly acidic conditions；When P is substituted or unsubstituted C1~6Carbonyl (such as formoxyl, acetyl group, benzoyl or chloromethyl acetyl group) time, the ester hydrolysis reaction that can pass through this area conventional be sloughed.
Slough nitroreduction in the compound 3 of hydroxyl protecting group P and become the reaction condition of amino; the method that those of ordinary skill in the art commonly use can be adopted; such as reacted by hydro-reduction; such as include but not limited to; with palladium dydroxide carbon for catalyst, with oxolane for solvent, under glacial acetic acid exists; hydro-reduction becomes amino, obtains compound 2.
It is further preferred that when compound 3 sloughs protection base P(such as, P is the benzyl of benzyl or replacement) condition when being hydro-reduction, the nitroreduction in compound 3 can be become amino simultaneously, namely by single step reaction, obtain compound 2.
Further, in said method, described compound 3 is by compound 4 cyclisation, changes into:
；
Preferred compound 4 is with N-Methyl pyrrolidone (NMP), toluene or dimethylbenzene for solvent, when reaction temperature is 100 DEG C ~ 200 DEG C, and cyclisation, change into compound 3；Preferred reaction solvent is NMP, and reaction temperature is 150 ~ 160 DEG C.
Further, in said method, described compound 4 is to be reacted by compound 5 and compound 6, generates:
；
Wherein, compound 5 and compound 6 are in suitable solvent (such as toluene, oxolane or its mixed solution), at acid binding agent (such as triethylamine, diisopropylethylamine or N-methylmorpholine) and catalyst (such as pyridine or N, N-lutidines) under existence condition, carrying out dehydration condensation, reaction temperature is preferably-20 DEG C ~ 20 DEG C；Further, it is preferable that using the mixed solution of toluene/THF as reaction dissolvent, employing N-methylmorpholine is acid binding agent, N, N-lutidines is catalyst, under-10 DEG C ~ 0 DEG C condition, compound 6 and compound 5 is carried out dehydration condensation, generates compound 4.In the mixed solution of described solvent toluene/THF, toluene can mix with any volume ratio with THF, it is preferable that described solvent is volume ratio is the mixed solution of toluene/THF of 1:1 ~ 10:1.
Further, in said method, described compound 6 is by reduction reaction by compound 7, changes into:
；
Three key in described compound 7 is reduced into the reaction of double bond containing compound 6, can reduce in accordance with conventional methods known in the art and obtain；Or preferably using oxolane, toluene, ethyl acetate, methanol, ethanol or water as solvent, under palladium charcoal catalytic hydrogenation conditions, compound 7 being reduced into compound 6, reaction temperature is preferably room temperature.
Further, in said method, described compound 7 is to be changed into by compound 8:
；
Above-mentioned steps is changed in the reaction of compound 7 by compound 8, it is preferable that make compound 8 and compounds X-CH2-O-P, at suitable solvent (such as toluene, ether, oxolane or 1,4-dioxane) in, under suitable alkalescence (such as n-BuLi, lithium diisopropylamine or lithium hexamethyldisilazide) condition, and at suitable temperature (such as-30 DEG C ~-80 DEG C), compound 7 is prepared in reaction, wherein compounds X-CH2The non-halogen of X in-O-P, P is substituted or unsubstituted C1~6Alkyl, benzyl, or the benzyl replaced by one or more substituent groups on phenyl ring, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro, document Synthesisandconversionsofoxygen-containingunsaturatedorg aniccompounds.XLIII.Synthesisandconversionsofsomeacetyle nehydroxyethers.Shikhiev, I.A.FromZhurnalOrganicheskoiKhimii, 4 (2), 247-9;1968, disclose similar reaction, disclosed in it, full content is incorporated by reference in the present invention.
In above-mentioned reaction, when P is substituted or unsubstituted C1~6Silylation (such as trimethyl silicon based, triethyl group is silica-based, t-Butyldimethylsilyl), substituted or unsubstituted C1~6Carbonyl (such as formoxyl, acetyl group, chloromethyl acetyl group) time; generally first compound 8 is changed into following formula: compound (8-1), then by compound (8-1) with corresponding carboxylic acid or alkyl silyl (such as, trimethylchloro-silicane; tert-butyldimethylsilyl chloride silicon etc.) reaction, obtain compound 7.Such as, compound 8, in the basic conditions (such as lithium methide, n-BuLi or KOH), at suitable solvent (such as THF, ether etc.) and formaldehyde reaction, prepares compound (8-1)；nullDocument Technologicalparametersofsynthesesfrom1-butyn-3-ol(Khimi cheskayaPromyshlennostSegodnya (2009),(6),12-16)，SynthesiswithTricarbonylironLactoneComplexes(Avail.SORD,OrderNo.1630259.(1989),Nopp.From:Sel.Org.React.Database (SORD) 1989) and Preparationoftwoaggressioncontrollingsubstancesinbees(Sk atteboel,Lars,ActaChemicaScandinavica,49(7),543-5;1995) disclosing similar preparation method, the content that it discloses is incorporated by reference in the present invention；
。
On the other hand, the preparation method that the present invention also provides for a kind of compound D:
Described compound D is that the compound A prepared by said method changes into, wherein, and R1It is the alkyl with 1 to 4 carbon atom, preferential R1It it is ethyl.
Further, in said method, described compound A changes into the step of compound D and includes, and compound A reacts with compound B,
Wherein, R2Selected from C1~C10Alkyl, aryl, heteroaryl and aralkyl, to produce compound D；Preferred R1、R2It is ethyl；Preferred compound A and compound B at suitable solvent (such as toluene, oxolane or 1,4-dioxane) in, in suitable alkalescence (such as n-BuLi, lithium diisopropylamine or lithium hexamethyldisilazide) condition, and react under proper temperature (such as-30 DEG C ~-80 DEG C) condition, prepare compound D；Further preferably suitable solvent is oxolane；Suitable alkali is n-BuLi, and suitable reaction temperature is-78 DEG C.
Further, the preparation method that the invention provides a kind of compound C:
,
Comprise the following steps:
(1) compound 8 is made to change into compound 7 in the basic conditions:
；
(2) compound 7 is by reduction reaction, prepares compound 6:
,
(3) compound 6 and compound 5 are by dehydrating condensation, prepare compound 4:
；
(5) compound 4 is through cyclization, prepares compound 3:
；
(6) compound 3 is by hydro-reduction, sloughs protection base P, and is amino by nitroreduction, obtains compound 2:
；
(7) compound 2 reacts with halogen formate ethyl ester, obtains compound 1:
；
(8) compound 1 is through peroxidization, prepares compound A:
(9) compound A and compound B is through coupling, prepares compound C:
。
Wherein, P is hydroxyl protecting group；Preferred described hydroxyl protecting group P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, substituted or unsubstituted C1~6Alkyl, benzyl, the benzyl replaced by one or more substituent groups, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro；Further preferred, described hydroxyl protecting group P is trimethyl silicon based, and triethyl group is silica-based, t-Butyldimethylsilyl, formoxyl, acetyl group, chloromethyl acetyl group, methyl, ethyl, propyl group, the tert-butyl group, ethoxyethyl group, benzyl, trityl or to methoxy-benzyl.In said method, the reaction condition corresponding synthetic method of similar compound D of step (1) ~ (9).
The third aspect, the invention provides such as the preparation method of following formula: compound 4,
,
Comprise the following steps:
Make compound 6 and compound 5 by dehydrating condensation, obtain compound 4:
。
Further, the preparation method of described compound 4, comprise the following steps:
(1) compound 8, is made to change into compound 7:
；
(2), compound 7 by reduction reaction, prepare compound 6:
,
(3), make compound 6 and compound 5 by dehydrating condensation, obtain compound 4:
；
Wherein, P is hydroxyl protecting group；Preferred described hydroxyl protecting group P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, substituted or unsubstituted C1~6Alkyl, benzyl, the benzyl replaced by one or more substituent groups, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro；Further preferred, described hydroxyl protecting group P is trimethyl silicon based, and triethyl group is silica-based, t-Butyldimethylsilyl, formoxyl, acetyl group, chloromethyl acetyl group, methyl, ethyl, propyl group, the tert-butyl group, ethoxyethyl group, benzyl, trityl or to methoxy-benzyl.
On the other hand, the invention provides following compound:
,
Wherein, P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, substituted or unsubstituted C1~6Alkyl, benzyl, the benzyl replaced by one or more substituent groups, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro；
With,
Wherein, R3For H or COOR4；Wherein R4Selected from C1~4Alkyl, the alkyl of halogen substiuted；
Further, the invention provides the compound of following structure:
、、、With；Wherein, P is selected from, benzyl, and to methoxy-benzyl, triphenylbenzylphosphonium, trimethyl silicon based, t-Butyldimethylsilyl, triethyl group is silica-based, acetyl group, the tert-butyl group and methyl.
More specifically, in some embodiments, the preparation method of compound A provided by the present invention and compound D can represent with following reaction equation:
。
Wherein, R1It is the alkyl with 1 to 4 carbon atom, R2Selected from R2Selected from C1~C10Alkyl, aryl, heteroaryl and aralkyl, P is hydroxyl protecting group；Preferably, P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, substituted or unsubstituted C1~6Alkyl, benzyl, the benzyl replaced by one or more substituent groups, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro；It is furthermore preferred that P is trimethyl silicon based, triethyl group is silica-based, t-Butyldimethylsilyl, formoxyl, acetyl group, chloromethyl acetyl group, methyl, ethyl, propyl group, the tert-butyl group, ethoxyethyl group, benzyl, trityl or to methoxy-benzyl；Further, it is preferable that R1、R2Being ethyl, P is benzyl.
Use herein or technical staff has otherwise known following definition and term.Unless otherwise, these definition are applicable to entire description and claims.Chemical name, popular name and chemical constitution are interchangeable for describing identical structure.Therefore, the definition of " alkyl " is for " alkyl " part of " alkyl " and " hydroxyalkyl ", " haloalkyl ", " alkoxyl " etc..
The alkyl with 1 to 4 carbon atom of the present invention, the alkyl of 1 to 10 carbon atom is such as methyl, ethyl, propyl group or butyl, C1~6Alkyl includes straight chained alkyl and branched alkyl, for instance the straight chained alkyl with 1 to 4 carbon atom includes methyl, ethyl, n-pro-pyl, normal-butyl；Alkyl containing side chain includes isopropyl, the tert-butyl group, 2-methyl butyl etc..
Described " alkoxyl " refers to allcyl-O-groups, and described alkyl is described above.C1~6Alkoxyl is for example, it may be methoxyl group, ethyoxyl, positive propoxy, isopropoxy, butyl oxygen base or tert-butoxy etc..
Described " halogen " includes F, Cl, Br and I.
Compound B used in the present invention:
, wherein, R2Selected from C1~C10Alkyl, aryl, heteroaryl and aralkyl, can according to the compound 116 in patent CN101511852B and CN101511852B(i.e. patent) disclosed in concrete grammar prepare, the full content of these patent disclosure is incorporated by reference into the present invention.
The compound 5 of the present invention:
, compound 5 can be prepared according to following schemes by acrylic aldehyde and Nitrocarbol.；With inorganic base, for instance, metal hydroxides (such as, LiOH, KOH, NaOH, Ca (OH)2), metal carbonate (such as, Li2CO3、Na2CO3、K2CO3、CS2CO3) and acrylic aldehyde at C1-C8Alcohol (such as, methanol, ethanol, propanol, isopropanol, butanol, sec-butyl alcohol, the tert-butyl alcohol, amylalcohol and capryl alcohol) or the mixture of alcohol process Nitrocarbol., obtains crude compound 8.For purifying compounds 8, by with selected from NaHSO3、KHSO3、Na2S2O5And K2S2O5Metal bi-sulfite agent treated, make crude compound 8 be separated into its metal bi-sulfite 9.By with containing water and with the lower alkyl carbonyl compound (such as, the salt of acetaldehyde, acetone, glyoxalic acid or glyoxalic acid) in the two-phase system of the solvent of water immiscibility and carbonate bases (such as, LiHCO3、NaHCO3、KHCO3、Na2CO3、K2CO3) process, make bisulfite compound 9 be converted into the compound 8 of purification.
By with inorganic solvent (such as, CH2Cl2, chlorobenzene, t-butyl methyl ether or toluene) in secondary amine (such as, piperidines, pyrrolidine, piperazine, dialkylamine and two aralkylamines) and carboxylic acid (such as, aliphatic series and aromatic carboxylic acid) process, cyclizing compounds 8, generate compound 10.
Make compound 10 be converted into compound 6 and have two kinds of methods, referred to herein as method C and method D.In method C, by making 10 and Wittig reagent reacting, compound 10 is first made to be converted into compound 6A.The R8 in Wittig reagent given in following schemes is selected from C1-C10 alkyl or aralkyl.Then through inorganic base or acid-catalyzed hydrolysis, compound 6A is made to be converted into compound 6.It is saline and alkaline that applicable inorganic base includes, but not limited to alkaline hydrated oxide, carbonate and phosphoric acid.Applicable acid includes, but not limited to inorganic and organic acid.
In method D, by, in suitable solvent or solvent mixture (such as, hydrocarbon solvent includes halogenated solvent, arsol and nitrogen-containing solvent), making compound 10 react with malonic acid, make compound 10 be converted into compound 6.In certain embodiments, solvent is pyridine or toluene or their mixture.Optionally, catalyst (such as, piperidines, pyrrolidine, piperazine, pyridine and triethylamine) can be introduced, to accelerate reaction.
The concrete preparation method of the publication number above-claimed cpd 5 that has been the patent disclosure of CN101193880B, the content of this patent disclosure is incorporated by reference in the present invention.
The present invention provides the improvement preparation method of a kind of compound A and the improvement preparation method of compound C and compound D, method provided by the invention, and syntheti c route is short, and operating procedure is simple, used intermediate stable in properties, it is easy to purification；The scheme preparing compound A provided by the invention does not need through carboxylic acid is reduced into aldehyde, but directly corresponding alcohol (compound 5 in the present invention program) is oxidized to corresponding aldehyde, operation safety, avoid carboxylic acid in prior art and first change into acyl chlorides when being usually catalytically hydrogenated to aldehyde again through palladium catalyst, it is necessary to use the harsh conditions of anhydrous palladium charcoal；More pleasantly surprised, in the present invention, when the benzyl that hydroxyl protecting group P is benzyl or replacement, while sloughing the protection base P of alcohol, nitroreduction can be become amino, simplify reactions steps, conservation and reagent, reduce production cost.It addition, operability of the present invention is high, safety improves, and easy and simple to handle, yield is higher, less costly, is suitable for industrialized production.
Specific embodiment:
Below in conjunction with specific embodiment, present invention and other aspect advantages are done further explaination.
Embodiment 1: the preparation of compound 7
In 1L there-necked flask, it is sequentially added into oxolane 60mL and concentrated sulphuric acid 10 μ L, under stirring, adds compound8(10g, 0.14mol) and hexamethyldisiloxane (11.5g, 0.07mol), after nitrogen replaces three times, be warming up to 60 DEG C of back flow reaction 3h.Reactant liquor is slowly cooled to-40 DEG C be simultaneously introduced oxolane 272mL, temperature control less than-30 DEG C drips n-BuLi (2.5M in normal hexane, 68.5mL, 0.17mol), after dripping off, temperature control less than-30 DEG C drips chloromethyl benzyl oxide (26.8g again, toluene (110mL) solution 0.17mol), drips off stirring 1h.React with water (20mL) cancellation, filter, after ethyl acetate washing leaching cake, be incorporated to filtrate, filtrate is drawn and after doing, obtains weak yellow liquid 20.4g through column chromatography purification, yield: 75.25%.1HNMR(400MHz, CDCl3-d1): δ 1.47(d, 3H), δ 2.86(brs, 1H) and, δ 4.19(d, 2H), δ 4.54-4.66(m, 3H) and, δ 7.26-7.36(m, 5H)；MS[M+H]+: 191.
Embodiment 2: the preparation of compound 6
It is sequentially added into compound in 500mL there-necked flask7(5%Pb lays poison, 1.9g5%Pd/CaCO for (19g, 0.1mol), Lindlar catalyst3, 0.018mol) and ethyl acetate 380mL, replaces three times through nitrogen, after hydrogen exchange three times, normal pressure 25 DEG C stirring 5h.Filtration of catalyst, is incorporated to filtrate after ethyl acetate washing leaching cake, filtrate is drawn and dry obtains weak yellow liquid 18.4g, yield: 95.83%.MS[M+H]+: 193.
Embodiment 3:The preparation of compound 4
It is sequentially added into compound in 250mL there-necked flask5(10g, 0.05mol) and toluene 50mL, suspension is cooled to 0 DEG C, and temperature control less than 5 DEG C is slowly added into toluene (25mL) solution of N-methylmorpholine (10.5g, 0.10mol) and trimethyl-aceyl chloride (6g, 0.05mol), drips off rear 0 DEG C of stirring 1h.Temperature control less than 5 DEG C is slowly added into compound6The toluene (40mL) of (9.6g, 0.05mol) and oxolane (22mL) solution, be subsequently added oxolane (6mL) solution of 4-dimethylaminopyridine (0.61g, 0.005mol), stirs mixed liquor 12h at about 0 DEG C.4NH is added after having reacted2SO4(25mL) solution cancellation reaction, is warming up to and stirs 1h less than 25 DEG C, filter, and filter cake ethyl acetate is washed three times, separates each layer, is incorporated to organic layer after ethyl acetate (2*25mL) aqueous layer extracted, and organic layer uses 5%K successively2CO3Solution (3*30mL), 5%NaCl(3*30mL) washing, slough solvent after drying through anhydrous sodium sulfate, obtain rufous liquid 15.8g, yield: 85.18%.1HNMR(400MHz, CDCl3-d1): δ 1.23-1.27(s, 1H), δ 1.32-1.37(d, 3H) and, δ 2.17-2.21(m, 1H), δ 2.27-2.31(m, 1H), δ 2.37-2.43(m, 2H), δ 2.77-2.78(s, 2H), δ 4.19-4.21(d, 2H), δ 4.49-4.55(d, 2H), δ 4.67-4.71(m, 1H), δ 5.55-5.60(t, 1H), δ 5.65-5.73(m, 2H), δ 5.74-5.81(d, 1H), δ 6.15(s, 1H), δ 7.26-7.34(m, 5H)；MS[M+H]+: 372.
Embodiment 4:The preparation of compound 3
It is sequentially added into compound in 250mL there-necked flask4(10g, 0.027mol) and N-Methyl pyrrolidone 100mL, after nitrogen replaces three times, be warming up to 160 DEG C of back flow reaction 7h.Reactant liquor is cooled to about 25 DEG C, adds 20mLDBU, stir 2h.Use 0.2NH2SO4(500mL) cancellation reaction, EA(500mL) extract, separate each layer, EA(3*100mL) wash water layer after be incorporated to organic layer, organic layers with water washes away N-Methyl pyrrolidone, purifies through column chromatography and obtain weak yellow liquid 7.46g after dry precipitation, yield: 74.6%.1HNMR(400MHz, CDCl3-d1): δ 0.85-0.90(m, 1H), δ 1.17-1.22(m, 1H), δ 1.24-1.29(d, 6H), δ 1.48-1.63(s, 6H), δ 4.04-4.18(m, 2H), δ 4.50-4.53(s, 2H), δ 4.57-4.61(m, 1H), δ 5.65-5.67(brs, 1H), δ 7.26-7.38(m, 5H)；MS[M+H]+: 372.
Embodiment 5:The preparation of compound 2
It is sequentially added into compound in 150mL hydriding reactor3(4g, 0.011mol), 15% palladium dydroxide carbon (59.6% humidity, 1g), oxolane 100mL and glacial acetic acid 1mL, nitrogen replaces three times, after hydrogen exchange three times, the lower 70 DEG C of back flow reaction 6h of 4atm.Reactant liquor is cooled to room temperature, Filtration of catalyst, and filtrate precipitation after drying obtains off-white color solid 2.34g, yield: 84.08%.MS[M+H]+: 254.
Embodiment 6:The preparation of compound 1
It is sequentially added into compound in 500mL there-necked flask2(25.3g, 0.1mol) and oxolane 250mL, nitrogen is replaced three times, add triethylamine (18.2g, 0.18mol), be cooled to-20 DEG C, temperature control less than-17 DEG C drips the THF(50mL of ethyl chloroformate (11.9,0.11mol)) solution ,-20 DEG C of stirring 1h after dripping off.After having reacted, add 12%H2SO4(250mL), DCM(250mL) extract, separate each layer, DCM(150mL*2) wash water layer after be incorporated to organic layer, organic layer uses 12%H successively2SO4, saturated sodium-chloride washing, anhydrous sodium sulfate dries, and obtains off-white color solid 27.3g, yield 84% after precipitation.MS[M+H]+:326。
Embodiment 7: the preparation of compound I
It is sequentially added into DMSO(0.9g, 11.06mmol in 100mL there-necked flask) and dichloromethane 20mL, nitrogen is replaced three times, it is cooled to-78 DEG C, temperature control less than-78 DEG C drips the DCM(10mL of oxalyl chloride (1.1g, 8.30mmol)) solution, stirs 5min at-78 DEG C after dripping off.Temperature control less than-78 DEG C drips compound again1The DCM(20mL of (1.5g, 4.61mmol)) solution, stirs 2h at-78 DEG C after dripping off.With triethylamine (2.2g after having reacted, 22.13mmol) cancellation reaction, add water (50mL), EA(50mL) extract, separate each layer, EA(20mL*2) being incorporated to organic layer after washing water layer, organic layer washs through saturated sodium-chloride, the dried precipitation of anhydrous sodium sulfate obtains white solid 1.2g, yield: 80.5%.1HNMR(400MHz, CD3CN-d3): δ 0.92-1.03(m, 2H), δ 1.20(m, 6H) and, δ 1.27(d, 3H), δ 1.54(qd, 1H), δ 1.82(dt, 2H), δ 1.93(d, 2H), δ 2.50(dt, 1H), δ 2.67(m, 2H), δ 3.43(qt, 1H), δ 4.03(q, 2H), δ 4.69(m, 1H), δ 5.42(br, 1H), δ 9.74(d, 1H)；MS[M+H]+: 324.
Embodiment 8:The preparation of compound C
It is sequentially added into compound in 100mL there-necked flaskB(13g, 0.04mol) and oxolane 30mL, be cooled to less than-20 DEG C by reactant liquor, is slowly added dropwise lithium diisopropylamine (2M, 20mL), and nitrogen is replaced three times, and-20 DEG C of stirring 1h obtain solution a.It is sequentially added into compound in another 100mL there-necked flaskI(10g, 0.03mol) and oxolane 75mL, stirring 30min obtains solution b.Solution b is slowly added in solution a by temperature control less than-20 DEG C ,-20 DEG C of stirring 1h after adding.(20mL) cancellation that adds water is reacted, and reactant liquor is warming up to 0 DEG C, uses 25%H2SO4(11mL) pH to about 7 is regulated.Reactant liquor is continuously heating to 20 DEG C and dilutes with ethyl acetate (100mL), water (70mL).Separating each layer, be incorporated to organic layer after ethyl acetate (50mL) aqueous layer extracted, the dry precipitation of organic layer obtains off-white color solid.This type of white solid ethanol is dissolved, at 35 ~ 40 DEG C, adds a crystal seed make compoundCCrystallization, then be cooled to 0 DEG C stirring 1h, filter, filter cake with cold washing with alcohol be placed in vacuum drying oven 50 DEG C dry, obtain white solid 12.7g, yield 83%.1HNMR(400MHz, CDCl3-d1null): δ 0.84(m，1H)，δ 0.98(m，1H)，δ 1.14(t，3H)，δ 1.19(m，4H)，δ 1.30(d，3H)，δ 1.76(m，4H)，δ 2.33(m，2H)，δ 2.66(m，1H)，δ 3.29(m，1H)，δ 3.95(dd，2H)，δ 4.85(dd，1H)，δ 6.58(d，1H)，δ 6.68(dd，1H)，δ 7.08(d，1H)，δ 7.25(dt，1H)，δ 7.51(d，1H)，δ 7.55(m，1H)，δ 7.61(d，1H)，δ 7.64(d，1H)，δ 8.10(dd，1H)，δ 8.88(d，1H)；MS[M+H]+: 493.
Embodiment 9: prepared compound 2 by compound 8
1), the preparation of compound (7-1): be sequentially added into absolute ether 60mL in 1L there-necked flask, add compound under stirring8(10g, 0.14mol) and hexamethyldisiloxane (11.5g, 0.07mol), after nitrogen replaces three times, be warming up to 60 DEG C of back flow reaction 3h.Reactant liquor is slowly cooled to-40 DEG C be simultaneously introduced absolute ether 272mL, temperature control less than-30 DEG C drips CH3OCH22.5M in Cl(normal hexane, 68.5mL, 0.14mol), after dripping off, temperature control less than-30 DEG C drips chloromethyl ether (26.8g, 0.17mol) again, after reaction terminates, react with water (20mL) cancellation, filter, after ethyl acetate washing leaching cake, be incorporated to filtrate, filtrate is drawn dry after purify through column chromatography and to obtain weak yellow liquid, for compound (7-1) yield: 77.25%.MS[M+H]+: 129.
2), the preparation of compound (3-1): the method being referred to embodiment 2 ~ 4 is prepared compound (3-1) by compound (7-1) through three-step reaction.
3), prepared compound 2 by compound (3-1): be sequentially added in 150mL hydriding reactor compound (3-1)(0.011mol), 15% palladium dydroxide carbon (59.6% humidity, 1g), oxolane 100mL and glacial acetic acid 1mL, nitrogen replaces three times, after hydrogen exchange three times, the lower 70 DEG C of back flow reaction 6h of 4atm.Reactant liquor is cooled to room temperature, Filtration of catalyst, and filtrate precipitation after drying obtains off-white color solid 2.4g, yield: 82%；
Above-mentioned off-white color solid (2.4g, 0.01mol) is joined in dichloromethane solution, then slowly drips boron chloride, in-4 ~ 7 DEG C of reactions, after reaction terminates, filter, dry, obtain off-white color solid, be compound 2, yield 97%.
Embodiment 10Compound (8-1) is prepared by compound 8
By the compound 8(71.5mmol of 100ml) THF solution be cooled to-50 DEG C, it is slowly added into 62.5ml2.29M(143mmol) diethyl ether solution of lithium methide, stir about 20min, it is slowly added into formaldehyde (71.5mmol), after stirring 1h, in 0 DEG C overnight, it is subsequently poured into the saturated NH4Cl(aq of the 100ml being chilled to 0 DEG C in advance) in, it is subsequently added saturated sodium-chloride, ether extracts (6*60ml), magnesium sulfate dries, concentration, obtains target compound (8-1).
Embodiment 11Compound 2 is prepared by compound (8-1)
1), compound (7-2) is prepared by compound (8-1):
Be sequentially added in 250mL there-necked flask compound (8-1)(10.0g, 0.1mol) and acetonitrile 80mL, nitrogen protection, be cooled to-10 DEG C, dropping acetic anhydride (10.2,0.1mol) ,-10 DEG C of stirring 6h after dripping off.After having reacted, add 7%NaHCO3(250mL), TBME(250mL) extract, separate each layer, TBME(150mL*2) and it being incorporated to organic layer after aqueous layer extracted, organic layer uses 7%NaHCO successively3, saturated sodium-chloride washing, anhydrous sodium sulfate dries, and obtains compound (7-2) 9.95g, yield 70%, MS [M+H] after precipitation+:143。
2) compound (3-2) is prepared by compound (7-2): prepared compound (3-2) by compound (7-2) through three-step reaction according to embodiment 2 ~ 4 method.
3), compound 2 is prepared by compound (3-2):
It is sequentially added into compound in 250mL hydriding reactor3-2(8.0g, 0.025mol), 15% palladium dydroxide carbon (59.6% humidity, 2g), oxolane 100mL and glacial acetic acid 1mL, nitrogen replaces three times, after hydrogen exchange three times, the lower 70 DEG C of back flow reaction 12h of 4atm.Reactant liquor is cooled to room temperature, Filtration of catalyst, is concentrated into 50mL, add 3N sodium hydrate aqueous solution, stirring 2h under room temperature, t-butyl methyl ether (250ml*2) extracts, and anhydrous sodium sulfate dries, and filters, concentration obtains compound (2) 4.76g, yield: 76.0%, MS [M+H]+: 254.
Embodiment 12Compound 2 is prepared by compound (8-1)
1), compound (7-3) is prepared by compound (8-1):
Be sequentially added in 250mL there-necked flask compound (8-1)(10.0g, 0.1mol) and acetonitrile 80mL, nitrogen protection, be cooled to-10 DEG C, dropping t butyldimethylsilyl chloride (15.1,0.1mol) ,-10 DEG C of stirring 5h after dripping off.After having reacted, add 7%NaHCO3(250mL), TBME(250mL) extract, separate each layer, TBME(150mL*2) and it being incorporated to organic layer after aqueous layer extracted, organic layer uses 7%NaHCO successively3, saturated sodium-chloride washing, anhydrous sodium sulfate dries, and obtains compound (7-3) 15.65g, yield 73%, MS [M+H] after precipitation+:215。
2) compound (3-3) is prepared by compound (7-3): prepared compound (3-3) by compound (7-3) through three-step reaction according to embodiment 2 ~ 4 method.
3), compound 2 is prepared by compound (3-3):
It is sequentially added into compound in 250mL hydriding reactor3-2(8.0g, 0.02mol), 15% palladium dydroxide carbon (59.6% humidity, 2g), oxolane 100mL, nitrogen replaces three times, after hydrogen exchange three times, the lower 70 DEG C of back flow reaction 12h of 4atm.Reactant liquor is cooled to room temperature, Filtration of catalyst, is concentrated into 50mL, add 1N tetrabutyl ammonium fluoride aqueous solution, stirring 1h under room temperature, t-butyl methyl ether (250ml*2) extracts, and anhydrous sodium sulfate dries, and filters, concentration obtains compound (2) 4.10g, yield: 81.0%, MS [M+H]+: 254.
Although the present invention is described already in connection with specific embodiment scheme given above, but its many changes, modifications and variations are apparent from for those of ordinary skill in the art.All these change, modifications and variations both fall within the spirit and scope of the present invention.
Claims (17)
1. the preparation method of compound A:
,
It is characterized in that, described compound A is through peroxidization by compound 1, changes into,
,
Wherein, R1It it is the alkyl with 1 to 4 carbon atom.
2. method according to claim 1, it is characterised in that described compound 1 is to be reacted with alkyl halo-formiates by compound 2, changes into:
。
3. method according to claim 2, it is characterised in that described compound 2 is by compound 3, changes into:
,
Wherein, P is hydroxyl protecting group.
4. method according to claim 3, it is characterised in that described compound 3 is by compound 4 cyclisation, changes into:
。
5. method according to claim 4, it is characterised in that described compound 4 is to be reacted by compound 5 and compound 6, generates:
。
6. method according to claim 5, it is characterised in that described compound 6 is by reduction reaction by compound 7, changes into:
。
7. method according to claim 6, it is characterised in that described compound 7 is to be changed into by compound 8:
。
8. according to the arbitrary described method of claim 3 ~ 7, it is characterised in that described hydroxyl protecting group P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, substituted or unsubstituted C1~6Alkyl, benzyl, the benzyl replaced by one or more substituent groups, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro.
9. method according to claim 8, it is characterised in that described hydroxyl protecting group P is trimethyl silicon based, and triethyl group is silica-based, t-Butyldimethylsilyl; formoxyl, acetyl group, chloromethyl acetyl group, methyl, ethyl; propyl group, the tert-butyl group, ethoxyethyl group, benzyl, trityl or to methoxy-benzyl.
10. method according to claim 7, it is characterised in that compound 8 changes into the step of compound 7, also includes first being changed into by compound 8 compound (8-1), then is reacted with hydroxy-protecting agent by compound (8-1), changes into compound 7,
,
Wherein, described hydroxyl protecting group P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro.
11. the preparation method of a compound D:
It is characterized in that, described compound D is that the compound A prepared by the arbitrary described method of claim 1 ~ 7 changes into.
12. method according to claim 11, it is characterised in that described compound A changes into the step of compound D and includes, compound A prepared by the arbitrary described method of claim 1 ~ 7 is made to react with compound B,
Wherein, R2Selected from C1~C10Alkyl, aryl, heteroaryl and aralkyl, to produce compound D.
13. the preparation method of a compound C:
,
Comprise the following steps:
Compound 8 is made to change into compound 7:
；
(2) compound 7 is by reduction reaction, prepares compound 6:
,
(3) compound 6 and compound 5 are by dehydrating condensation, prepare compound 4:
；
(5) compound 4 is through cyclization, prepares compound 3:
；
(6) compound 3 is by being amino by nitroreduction, and sloughs protection base P, obtains compound 2:
；
(7) compound 2 reacts with halogen formate ethyl ester, obtains compound 1:
；
(8) compound 1 is through peroxidization, prepares compound A:
(9) compound A and compound B is through coupling, prepares compound C:
。
14. a preparation method for compound 4,
,
Comprise the following steps:
Make compound 6 and compound 5 by dehydrating condensation, obtain compound 4:
。
15. the preparation method of compound 4 according to claim 14, it is characterised in that comprise the following steps:
(1) compound 8, is made to change into compound 7:
；
(2), compound 7 by reduction reaction, prepare compound 6:
,
(3), make compound 6 and compound 5 by dehydrating condensation, obtain compound 4:
。
16. the arbitrary compound in following formula:
,
Wherein, P is substituted or unsubstituted C1~6Silylation, substituted or unsubstituted C1~6Carbonyl, substituted or unsubstituted C1~6Alkyl, benzyl, the benzyl replaced by one or more substituent groups, described substituent group is selected from: C1~6Alkyl, C1~6Alkoxyl, phenyl, halogen and nitro；
With,
Wherein, R3For H or COOR4；Wherein R4Selected from C1~4Alkyl, the alkyl of halogen substiuted.
17. one kind selected from following compound
、、、With；Wherein, P is selected from, benzyl, and to methoxy-benzyl, triphenylbenzylphosphonium, trimethyl silicon based, t-Butyldimethylsilyl, triethyl group is silica-based, acetyl group, the tert-butyl group and methyl.
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