CN104892555A - Preparation method for treprostinil intermediate - Google Patents
Preparation method for treprostinil intermediate Download PDFInfo
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- CN104892555A CN104892555A CN201510093682.XA CN201510093682A CN104892555A CN 104892555 A CN104892555 A CN 104892555A CN 201510093682 A CN201510093682 A CN 201510093682A CN 104892555 A CN104892555 A CN 104892555A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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Abstract
The invention relates to a preparation method for a treprostinil intermediate (I). The preparation method comprises the steps that: a compound of a formula (II) and a compound of a formula (III) or acidic salt thereof react in the presence of a condensing agent to obtain a compound of a formula (IV); the compound of the formula (IV) and a compound of a formula (V) react to obtain a compound of a formula (I). According to the preparation method for the treprostinil intermediate, weinreb amide and alkyne negative ions react to directly obtain a ketone compound (I), so that environment pollution caused by heavy metal (a PCC oxidant) is avoided, and the adoption of a butyl lithium low-temperature reaction method is also avoided. The preparation method for the treprostinil intermediate has the advantages that reaction conditions are mild, the yield is high, the purity of products is high, and the industrial application prospect is wide. (Formulae (I), (II), (III), (IV) and (V) are shown in the specification)
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to the preparation method of your intermediate of a kind of treprostinil.
Background technology
Pulmonary hypertension (PAH) is disease or the pathologic, physiologic syndrome of the abnormal rising of pulmonary artery internal pressure that a class is caused by known or unknown cause, formed with the arteriolar vasospasm of lung, intimal hyperplasia, middle level plumpness, adventitia hyperplasia, primary thrombus, inflammation in various degree and plexi change etc. for feature, clinical manifestation is that Ppa pulmonary artery pressure Progressive symmetric erythrokeratodermia raises and finally causes right heart failure.Pulmonary hypertension is the very poor cardiovascular disorder of a kind of prognosis, sickness rate is low, 1 ~ 2 people's morbidity is had in Europe and the annual every million people of the U.S., for rare disease, the Case definition that WHO defines PAH is: under quiescent condition, mean pulmonary arterial pressure is greater than 25mmHg (1mmHg=0.133kPa), be greater than 30mmHg under kinestate, domesticly there is no definite epidemiologic data.
Existing medicine aspect, external existing multiple specificity UT-15 thing listing, comprises raw smooth class medicine (BSF208075, bosentan), 5 type phosphodiesterase inhibitors (Virga, Tadalafil), prostacyclin class medicine (Iloprost, treprostinil you, prostaglin X).The domestic specific treatment medicine for pulmonary hypertension is little, only have Iloprost (commodity order: Wan Tawei), bosentan (trade(brand)name: Quan Keli), ambrisentan sheet (all Rakes) get permission listing, current medicine exist the transformation period short, must by being placed on the permanent catheter in vena cava, adopt administration pump Intravenous Infusion, infusion interruption and bloodstream infection etc. may be caused.Therefore, existing sitaxsentan sodium thing is difficult to meet clinical demand, in the urgent need to introducing new active drug.
Your injection liquid of treprostinil is one of effective injection formulations for the treatment of pulmonary hypertension, and overseas clinical trial data presentation this product clinical efficacy is definite, security is better than other prostacyclin analogs class medicines gone on the market.Go on the market for many years in the U.S., Canada, Australia and Europe, and multiple countries listing in Asia.This product stability is better, long half time, and the administration of main employing subcutaneous continuous infusion mode, also sustainable intravenous infusion administration, transdermal delivery mechanisms is comparatively safe, can reduce the risk of severe infections septicemia.
Treprostinil that is researched and developed by American Association drugmaker (United Therapeutics), and in country's listings such as the U.S., be the medicine of prostanoid treatment pulmonary hypertension, its compound patent US4306075A is expired.1999, United Therapeutics house journal application WO9921830A1 disclosed a kind of method preparing treprostinil that, and the synthetic route of report is as follows:
And periodical J.Org.Chem.2004,69, the 1890-1902 preparation technologies optimizing WO9921830A1 report, and disclose the preparation method of side chain compound 6:
In above-mentioned preparation method, the difficult point of technique is the condensation reaction of compound 5 and compound 6, and therefore, compound 8 prepares your key intermediate of treprostinil, in this preparation method, there is following defect:
1, due to when preparing compound 8, each intermediate is oily matter, and purifying products difficulty, repeatedly need carry out column chromatography, and solvent consumption is large, causes cost increase and environmental protection pressure is large.
2, Claisen rearrangement reaction is for pyroreaction, the unstable of aldehyde compound itself and react for a long time at high temperature and can produce a large amount of by product polymer oily matter, must pass through column chromatography and removes oily matter, complex operation.
3, the heavy metal used during PCC oxidation causes environmental pollution serious, and easily causes product heavy metals exceeding standard.
Use n-Butyl Lithium on the one hand when 4, preparing compound 6, and need-40 DEG C--50 DEG C of reactions, use price trimethyl silicane propine costly in addition, cause compound 6 high cost, severe reaction conditions, industrial application value is low.
Summary of the invention
In order to solve prior art Problems existing, contriver develops a kind of method preparing your key intermediate (I) of treprostinil of novelty in long-term R&D process, and reaction conditions of the present invention is gentle, technical maturity, steady quality, is very suitable for industrial application.
One aspect of the present invention provides a kind of preparation method of formula I compound, comprises the steps:
1) formula II compound and formula III compound or its acid salt are obtained by reacting formula IV compound under condensing agent exists;
2) formula IV compound and formula (V) compound are obtained by reacting formula I compound, and reaction formula is as follows:
Wherein, R
1, R
2be independently hydroxyl protecting group separately.
As preferred scheme, R
1, R
2independently be selected from C separately
1-8alkyl, C
1-8alcoxyl C
1-8alkyl, halogen replace C
1-8alkyl, C
3-8cycloalkyl, benzyl, C
1-8alkoxyl group substituted benzyl, THP trtrahydropyranyl ,-SiR
3r
4r
5,-C (O) R
3; R
3, R
4, R
5independently be selected from C separately
l-8alkyl, C
3-8cycloalkyl.
As further preferred scheme, R
1for benzyl, R
2for 2-THP trtrahydropyranyl.
As preferred scheme, the acid of described formula III compound acid salt refers to organic acid or mineral acid, and described organic acid is selected from trifluoroacetic acid, trichoroacetic acid(TCA), methanesulfonic, trifluoromethanesulfonic acid, tosic acid or its mixture; Mineral acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, hydrofluoric acid, hydroiodic acid HI, formic acid, acetic acid or its mixture.
As further preferred scheme, the acid of described formula III compound acid salt is selected from hydrochloric acid.
As preferred scheme, described condensing agent is selected from DIC, DCC, HOBT, EDC.HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or its mixture.
As preferred scheme, step 2) in the Grignard reagent added relative to formula IV compound 0.5-10 times of molar weight, the Grignard reagent of preferred 1.0-2.0 times molar weight, described Grignard reagent preferable methyl magnesium bromide, ethylmagnesium bromide, methylmagnesium-chloride, ethylmagnesium chloride.
Further, described formula II compound can be obtained by following preparation method:
Wherein R
1as formula I compound define, R
6be selected from and replace or do not replace C
1-8alkoxyl group, replacement or do not replace C
3-8cycloalkyloxy, described substituting group is selected from halogen, C
1-8alkyl, C
1-8alkoxyl group, C
3-8cycloalkyl, C
3-8cycloalkyloxy, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, C
5-10aryl, C
5-10aryloxy, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base; Described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate or its mixture.
Further, described formula (Ⅸ) compound can be obtained by following preparation method again:
Wherein R
1as formula I compound define, R
6as above single step reaction Chinese style (Ⅸ) compound defined; Described alkali is organic bases or mineral alkali, described organic bases is selected from Trimethylamine 99, triethylamine, pyridine, piperidines, morpholine or its mixture, and described mineral alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium-acetate or its mixture;
Further, described formula (VIII) compound can be obtained by following preparation method again:
Wherein R
6as above single step reaction Chinese style (Ⅸ) compound defined, preferred methoxyl group, oxyethyl group; X is halogen, preferred bromine.
Further, described formula (V) compound can be obtained by following preparation method: be that described formula (V) compound prepared by raw material with formula (Ⅺ) compound, preparation method is as follows:
Or,
Or,
Wherein R
2, R
3, R
4, R
5as formula I compound define, X is halogen
Further, described formula (Ⅺ) compound can be obtained by following preparation method:
The present invention provide on the other hand a kind of with (S)-1,2-oxepane be the method for raw material preparation formula (V) compound, comprise the steps:
Wherein R
2as formula I compound define; X is halogen.
As preferential scheme, work as R
2when being selected from 2-THP trtrahydropyranyl (THP), its concrete preparation method is as follows:
The present invention provide on the other hand a kind of with (S)-1,2-oxepane be the method for raw material preparation formula (V) compound, comprise the steps:
Wherein R
2, R
3, R
4, R
5as formula I compound define.
As preferential scheme, work as R
2when being selected from 2-THP trtrahydropyranyl, its concrete preparation method is as follows:
The present invention provide on the other hand a kind of with (S)-1,2-oxepane be the method for raw material preparation formula (V) compound, comprise the steps:
Wherein R
2as formula I compound define; X is halogen.
As preferential scheme, work as R
2when being selected from 2-THP trtrahydropyranyl, its concrete preparation method is as follows:
Another aspect of the invention provides a kind of novel intermediates formula IV compound preparing formula I compound:
Wherein, R
1be selected from C
1-8alkyl, C
1-8alcoxyl C
1-8alkyl, halogen replace C
1-8alkyl, C
3-8cycloalkyl, benzyl, C
1-8alkoxyl group substituted benzyl, THP trtrahydropyranyl ,-SiR
3r
4r
5,-C (O) R
3; R
3, R
4, R
5independently be selected from C separately
l-8alkyl, C
3-8cycloalkyl.
As preferential scheme, R
1be selected from methyl, ethyl, the tertiary butyl or benzyl.
Compared with prior art, the present invention has following advantage:
1, the present invention prepares treprostinil that intermediate (I) employing two-step reaction, and reaction conditions is gentle, and intermediate (I) purity is greater than more than 95%, and prospects for commercial application is wide.
2, Claisen rearrangement byproduct of reaction of the present invention can by hydrolysis removing subsequently; it is solid that formula (VIII) compound obtains formula II compound after hydroxyl protection, Ester hydrolysis subsequently; easy recrystallization purifying; avoid column chromatography; and refining rear purity can reach more than 98%, is conducive to the carrying out of subsequent reactions.
3, a new compound and formula IV compound is obtained when the present invention prepares treprostinil you intermediate (I).
4, the present invention adopts weber acid amides and alkynes negative ion to react and directly obtains ketone compound (I), avoids in prior art the environmental pollution using heavy metal (PCC oxygenant) to cause.
5, the reaction of weber acid amides of the present invention and alkynes negative ion can be reacted under condition (room temperature to 45 DEG C) as mild as a dove by Grignard reagent, avoids industrial more difficult very low temperature reaction, simplifies operation, greatly reduce energy consumption.
6, the present invention is with (S)-1,2-oxepane formula (Ⅺ) compound provides three kinds of diverse ways preparation formula (V) compounds for raw material, the open loop of epoxide selectivities nucleophilic reaction is utilized to obtain single substituent, reaction conditions gentleness is easy and safe to operate, raw material and reagent simple and easy to get and cheap, products obtained therefrom GC purity can reach more than 90%, far above the GC purity of prior art report, is applicable to industrial application.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and hereafter (as embodiment)
In can combine mutually between specifically described each technical characteristic, thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
Describe in detail: unless stated to the contrary, following use term in the specification and in the claims has following implication.
" C
1-8alkyl " refer to the straight chained alkyl and the containg branched alkyl radical that comprise 1 to 8 carbon atom, alkyl refers to saturated aliphatic hydrocarbon group, C
0-8refer to not carbon atoms or C
1-8alkyl, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group or its various branched chain isomers etc.
Alkyl can be replacement or unsubstituted, and when substituted, substituting group can be substituted on any spendable tie point, is preferably one or more following group, independent selected from halo, C
1-8alkyl, C
1-8alkoxyl group, C
3-8cycloalkyl, C
3-8cycloalkyloxy, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, C
5-10aryl, C
5-10the substituting group of aryloxy, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base replaced;
" cycloalkyl " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, " C
3-8cycloalkyl " refer to the cycloalkyl comprising 3 to 8 carbon atoms, preferred monocyclic cycloalkyl, such as:
The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.
Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring." spiro cycloalkyl group " refers to the polycyclic moiety sharing a carbon atom (title spiro atom) between monocycle, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group by the number according to sharing spiro atom between ring and ring, and the non-limiting example of spiro cycloalkyl group comprises:
" cycloalkyl " refers to that each ring in system and other rings in system share the full carbon polycyclic moiety of a pair carbon atom adjoined, and wherein one or more rings can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl according to the number of makeup ring, the non-limiting example of cycloalkyl comprises:
" bridge ring alkyl " refers to that any two rings share the full carbon polycyclic moiety of two carbon atoms directly do not connected, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Can be divided into dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl according to the number of makeup ring, the non-limiting example of bridge ring alkyl comprises:
Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring wherein linked together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.
Cycloalkyl can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, C
1-8alkyl, C
1-8alkoxyl group, C
3-8cycloalkyl, C
3-8cycloalkyloxy, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, C
5-10aryl, C
5-10aryloxy, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base;
" cycloalkyloxy " refers to and-O-(unsubstituted cycloalkyl), and wherein the definition of cycloalkyl is described above.C
3-8cycloalkyloxy refers to the cycloalkyl oxy containing 3-8 carbon, and non-limiting example comprises ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
Alkoxyl group can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, C
1-8alkyl, C
1-8alkoxyl group, C
3-8cycloalkyl, C
3-8cycloalkyloxy, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, C
5-10aryl, C
5-10aryloxy, 5-10 unit heteroaryl, 5-10 unit heteroaryl oxygen base;
" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, wherein one or more annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) r (wherein r is integer 0,1,2), but do not comprise the loop section of-O-O-,-O-S-or-S-S-, all the other annular atomses are carbon." 5-10 unit heterocyclic radical " refers to the cyclic group comprising 5 to 10 annular atomses, and " 3-8 unit heterocyclic radical " refers to the cyclic group comprising 3 to 8 annular atomses.
" aryl " refers to full carbon monocycle or fused polycycle (namely sharing the right ring of adjacent carbon atoms) group, has many rings (namely it is with the ring of the phase adjacency pair carbon atom) group of the π-electron system of conjugation, " C
5-10aryl " refer to containing 5-10 carbon full carbon aryl, " 5-10 unit aryl " refers to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
" heteroaryl " refers to comprise 1 to 4 heteroatomic heteroaromatic system, described heteroatoms comprises the heteroatoms of nitrogen, oxygen and S (O) r (wherein r is integer 0,1,2), 5-7 unit heteroaryl refers to the heteroaromatic system containing 5-7 annular atoms, 5-10 unit heteroaryl refers to the heteroaromatic system containing 5-10 annular atoms, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:
" halogen " refers to fluorine, chlorine, bromine or iodine.
"-SiR
3r
4r
5" refer to trialkyl silyl, preferred trimethyl silicane, triethyl silicon, tert-butyldimethyl silyl etc.
Term " condensing agent " refers to the reagent that can cause condensation reaction.Condensation reaction refers to that two or more organic molecule synthesizes a macromole with covalently bonded after interacting, and loses the reaction of water or other fairly simple inorganic or organic molecules simultaneously.Small-molecule substance is wherein water, hydrogenchloride, methyl alcohol or acetic acid etc. normally.In the present invention, the Chinese of the abbreviation correspondence of various condensing agent is as shown in table 1.
The Chinese of the abbreviation correspondence of the various condensing agent of table 1
| Be called for short | Chinese |
| DIC | N, N-DIC |
| DCC | N, N-dicyclohexylcarbodiimide |
| HOBT | I-hydroxybenzotriazole |
| EDC.HCl | 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride |
| PyBOP | Phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl |
| PyBroP | Tripyrrole Wan base phosphonium bromide hexafluorophosphate |
| HATU | 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester |
| HCTU | 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester |
| DEPBT | 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4-ketone |
| EEDQ | 2-oxyethyl group-1-ethoxy carbonic acyl radical-1,2-dihydroquinoline |
| CDI | Carbonyl dimidazoles |
Below in conjunction with embodiment, the present invention is described in further detail and completely, but limit the present invention by no means, and the present invention is also not only confined to the content of embodiment.
Compound structure of the present invention by nucleus magnetic resonance (NMR) or/and LC-MS chromatogram (LC-MS) is determined.Nmr chemical displacement (δ) provides with the unit of 1,000,000/(ppm).The mensuration of NMR is that measuring solvent is deuterated dimethyl sulfoxide (DMSO-d with Bruker AVANCE-400 nuclear magnetic resonance spectrometer
6), deuterated methanol (CD
3and deuterochloroform (CDCl OD)
3) in be designated as tetramethylsilane (TMS).
The mensuration Agilent 1200Infinity Series mass spectrograph of LC-MS chromatogram LC-MS.The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 × 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150 × 4.6mm chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that TLC adopts is 0.15mm ~ 0.20mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.Column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
Starting raw material in the embodiment of the present invention is known and can have commercially bought, or can adopt or synthesize according to methods known in the art.
When without specified otherwise, of the present invention to respond all under continuous print magnetic stirs, carry out under drying nitrogen or argon atmospher, solvent is dry solvent.
When without specified otherwise, the solution in embodiment refers to the aqueous solution.The temperature of reaction is room temperature.Room temperature is optimum temperature of reaction, is 20 DEG C ~ 30 DEG C.
The monitoring of the reaction process in embodiment adopts tlc (TLC), liquid matter is used in conjunction chromatogram (LC-MS) or vapor-phase chromatography (GC) is reacted the developping agent system used and had: methylene dichloride and methanol system, normal hexane and ethyl acetate system, sherwood oil and ethyl acetate system, acetone, the volume ratio of solvent can regulate according to the polarity difference of compound.
The system of the eluent of column chromatography comprises: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: methylene dichloride and ethyl acetate system, D: ethyl acetate and methyl alcohol, the volume ratio of solvent regulates according to the polarity difference of compound, also can add a small amount of ammoniacal liquor and acetic acid etc. and regulate.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Embodiment one
1000ml methyl alcohol is added in nitrogen protection downhill reaction bottle, add compound 3-hydroxy-benzoic acid methyl ester 200.0g (1.314mol), salt of wormwood 218.0g (1.580mol), sodium iodide 20.0g (0.133mol), bromopropylene 191.0g (1.579mol) under stirring successively, be heated to backflow; After stirring reaction 7-9 hour, TLC detects raw material reaction complete (developping agent: sherwood oil: ethyl acetate=4:1), is cooled to 25 DEG C, by reacting liquid filtering, is evaporated to dry; 500ml methyl tertiary butyl ether is added to resistates, filter, filtrate is washed once with 15% aqueous ammonium chloride solution 300ml, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to doing to obtain pale yellow oil 3-allyloxy-benzoic acid methyl ester 243.5g (1.267mol, molar yield: 96.4%, HPLC purity 96.5%).
Embodiment two
3-allyloxy-benzoic acid methyl ester 243.5g (1.267mol) is placed in reaction flask, is warming up to 220 DEG C of reactions 1.0 ~ 3.0 hours, is cooled to 60 DEG C, the lithium hydroxide aqueous solution of 500ml methyl tertiary butyl ether and 844ml 1mol/L is added successively in above-mentioned reaction flask, temperature adjustment is spent the night to 30-40 DEG C of stirring reaction, be cooled to 0 ~ 5 DEG C, drip 117ml concentrated hydrochloric acid and adjust reaction solution pH=1 ~ 2, extract with 700ml methyl tertiary butyl ether, organic phase is successively through saturated sodium bicarbonate aqueous solution (700ml × 2), saturated sodium-chloride water solution (500ml) washs, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to doing to obtain pale yellow semi-solid 2-allyl group-3-hydroxy-benzoic acid methyl ester 193.8g (1.008mol, molar yield 79.6%, HPLC purity 96.4%).
Embodiment three
2-allyl group-3-hydroxy-benzoic acid methyl ester 193.8g (1.008mol) is placed in reaction flask, add 3000ml acetone, and then add sodium iodide 14.8g (0.099mol), cesium carbonate 393.4g (1.207mol), benzyl bromine 190.6g (1.112mol), be warming up to backflow.Stirring reaction 1-2 hour, TLC analyze raw material reaction complete (developping agent: sherwood oil: ethyl acetate=4:1), are cooled to room temperature, filter, are evaporated to dry; Add 300mL normal hexane, with water (200ml*3) washing, anhydrous sodium sulfate drying, filter, be evaporated to dry give light yellow oil 2-allyl group-3-benzyloxy-benzoic acid methyl ester 279.8g (0.991mol, molar yield 98.3%, HPLC purity 91.1%).
Embodiment four
2-allyl group-3-benzyloxy-benzoic acid methyl ester 279.8g (0.991mol) is placed in reaction flask, add 3000ml tetrahydrofuran (THF), 1000ml methyl alcohol successively, 15% potassium hydroxide aqueous solution 1115.3g (2.981mol), is heated to backflow; React after 4 hours, TLC analyzes raw material reaction complete (developping agent: sherwood oil: ethyl acetate=4:1), is cooled to 50 DEG C, concentrating under reduced pressure removing methyl alcohol and tetrahydrofuran (THF).Residual aqueous phase methyl tertiary butyl ether (600mL*3) extracts, divide water-yielding stratum, drip 3.0mol/L dilute hydrochloric acid (about 860mL) and regulate pH=1 ~ 2, drip off stirring reaction 1 hour, filter, filter cake 1500ml sherwood oil making beating stirring 0.5 hour, filter, filter cake 60 DEG C of vacuum-dryings obtain off-white color solid 2-allyl group-3-benzyloxy-phenylformic acid 222.8g (0.830mol, yield 83.8%, HPLC purity 99.0%) in 3 hours.
Embodiment five
Under nitrogen protection, by 2-allyl group-3-benzyloxy-phenylformic acid 40.0g (0.149moL) and N, O-dimethyl hydroxylamine hydrochloride 22.0g (0.224mol) is placed in reaction flask, then 80mL N is added, dinethylformamide, HOBT20.1g (0.149mol) is added successively under stirring, EDCI44.3g (0.224mol), N, N-diisopropylethylamine 67.4g (0.552mol), stirring at room temperature reacts 20 hours, TLC analyzes raw material reaction complete (developping agent: sherwood oil: ethyl acetate=4:1), be cooled to 0 ~ 5 DEG C, add 400mL methyl tertiary butyl ether, then 3% aqueous sodium hydroxide solution 335g is dripped, dropwise rear stirring 0.5 hour, separate upper organic layer, water layer adds the extraction of 400ml methyl tertiary butyl ether, merge organic phase, organic phase is washed through 1.2mol/L dilute hydrochloric acid (500ml × 2) successively, saturated sodium bicarbonate aqueous solution (300ml × 1) washs, anhydrous sodium sulfate drying, filter, 45 ~ 50 DEG C are evaporated to dry yellow oil 2-allyl group-3-benzyloxy-N-methoxy-. N-methyl-benzamide 45.3g (0.145mol, molar yield 97.6%, HPLC purity 98.1%).
1H NMR(400MHz,DMSO-d6):δ7.48-7.31(m,5H),7.25(t,J＝8Hz,1H),7.12(d,J＝8Hz,1H),6.87(d,J＝7.6Hz,1H),5.88-5.79(m,1H),5.15(s,2H),4.96-4.91(m,2H),3.44(br,3H),2.29-3.31(m,2H),3.22(br,3H).
Embodiment six
Under nitrogen protection room temperature condition; add (6S)-6-((tetrahydrochysene-2H-pyranyl-2-base) oxygen base)--9-alkynes 35.6g in last of the ten Heavenly stems (0.149mol) and 60mL tetrahydrofuran (THF) successively in reaction flask; stir lower dropping 3.0mol/L ethyl magnesium bromide etherate 50.8mL (0.152mol); dropwise temperature control 35 ~ 40 DEG C, stirring reaction 1.5-2.0 hour.Then temperature adjustment to 25 DEG C, add tetrahydrofuran (THF) (60mL) solution of 2-allyl group-3-benzyloxy-N-methoxy-. N-methyl benzamide 45.3g (0.145mol), finish and be warming up to back flow reaction 1 hour, TLC detects raw material reaction complete (developping agent: sherwood oil: ethyl acetate=4:1), be cooled to 0 ° ~ 5 DEG C, add 100ml saturated aqueous ammonium chloride cancellation reaction; With methyl tertiary butyl ether (200mL × 2) extraction mixed solution, merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, cross post and be separated to obtain pale yellow oil (6S)-1-(2-allyl group-3-(benzyloxy) phenyl)-6-((tetrahydrochysene-2H-pyranyl-2-base) oxygen)-undecyl-2-alkynes-1-ketone 55.2g (0.113mol, yield 77.9%, HPLC purity 98.1%).
1H NMR(400MHz,CDCl
3):δ7.78-7.73(m,1H),7.44-7.31(m,5H),7.29-7.24(m,1H),7.10(dd,J＝7.6,1.6Hz,1H),6.05-5.96(m,1H),5.11(s,2H),5.03-4.95(m,2H),4.66-4.61(m,1H),3.92-3.84(m,3H),3.76-3.71(m,1H),3.50-3.45(m,1H),2.64-2.59(m,1H),2.50(t,J＝7.6Hz,1H),1.92-1.25(m,16H),0.88(t,J＝6.8Hz,3H).
Embodiment seven
Magnesium chips 144.0g (6.0mol), 2000ml anhydrous tetrahydro furan, a small amount of iodine are joined in reaction flask, be heated to 50 DEG C, drip bromination of n-butane 548.1g (4.0mol), initiation reaction in dropping process, dark brown solution becomes colourless solution, control rate of addition, holding temperature 55 DEG C-60 DEG C, within 60 minutes, drip and finish.Be down to room temperature (25 DEG C) stirring reaction 2 hours.Leave standstill, separate supernatant liquor under nitrogen protection, obtain 2000ml grey black normal-butyl magnesium bromide tetrahydrofuran solution (about 2.0mol/L), stand-by.
By (S)-epoxy chloropropane 350g (3.78mol), cuprous iodide 72.37g (0.38mol) and 1000ml anhydrous tetrahydro furan join in another reaction flask bottle, are cooled to 0 DEG C and stir 10 minutes.Slowly be added drop-wise in above-mentioned reaction solution by the normal-butyl magnesium bromide tetrahydrofuran solution prepared, control rate of addition and make interior temperature lower than 10 DEG C, about 2h drips complete, is warming up to room temperature (25 DEG C) stirring reaction 16 hours, reacts completely.Be cooled to 0 DEG C.15% ammonia soln (600ml) the cancellation reaction that slow dropping ammonium chloride is saturated, control temperature, lower than 25 DEG C, finishes, and stirs 0.5 hour, suction filtration, and filter cake 1000ml ethyl acetate washing, merging filtrate organic phase, uses NH successively
415% ammonia soln (400ml) that Cl is saturated, the saturated NaCl aqueous solution (400ml) respectively wash once.50 DEG C are evaporated to dry oily matter (S)-1-chloroheptane-2-alcohol crude product 638.4g (GC purity 75.32%).
By (S)-1-chloroheptane-2-alcohol crude product (638.4g), 2000ml methyl tertiary butyl ether joins in another reaction flask, slowly add NaOH solid 370g (9.25mol) in batches, room temperature (25 DEG C) stirring reaction 18 hours, raw material primitive reaction is complete, suction filtration, filtrate uses water (400ml) successively, saturated aqueous common salt (200ml) respectively washs once, anhydrous sodium sulfate drying, 40 DEG C are evaporated to dry, concentrated gained oily matter decompression is heavily steamed, pressure-0.95mPa, collect 70-75 DEG C of cut, obtain colorless oil (S)-1, 2-oxepane 265.8g (2.329mol, molar yield 61.6%, GC purity 86.37%).
Embodiment eight
Under nitrogen protection condition; by (S)-1; 2-oxepane 80.0g joins in reaction flask; add 400ml tetrahydrofuran (THF) and CuI 13.4g (0.07mol) successively; be cooled to 0 ~ 5 DEG C, drip 515ml 1.7mol/L allylmgcl tetrahydrofuran solution (0.876mol), control rate of addition and keep reacting liquid temperature to be no more than 5 DEG C; within about 2 hours, dropwise, be incubated 0 DEG C and stir 1 hour.It is complete that GC detects raw material reaction.Slow dropping 15% ammonia water saturation NH
4cl solution (800ml) cancellation is reacted, and control temperature is no more than 30 DEG C.Dropwise, separate out a large amount of solid, suction filtration, filter cake 1000ml ethyl acetate washing, filtrate branch vibration layer, organic phase uses 15% ammonia water saturation NH successively
4cl solution (400mL), the saturated common salt aqueous solution (200mL) wash each washing once, anhydrous sodium sulfate drying, is evaporated to dry oily matter (S)-Xin-1-alkene-5-alcohol 108.8g (GC purity: 78.0%).
Embodiment nine
(S)-Xin-1-alkene-5-alcohol 108.8g is added in reaction flask, then 550ml methylene dichloride is added, stirring and dissolving, add 3 successively, 4-dihydro-2H-pyrans (DHP) 181.4g (2.16mol), para-methylbenzenepyridinsulfonate sulfonate (PPTs) 9.01g (0.03mol), room temperature (25 DEG C) stirring reaction 16-24 hour, raw material primitive reaction is complete, reaction solution is successively with saturated NaHCO3 solution (200ml × 2), saturated NaCl solution (200mL × 1) is washed, anhydrous sodium sulfate drying, suction filtration, be evaporated to dry oily matter 2-(((S)-Xin-1-alkene-5-base) oxygen) tetrahydrochysene-2H-pyrans 146.0g (GC purity: 69.0%).
Embodiment ten
By 2-(((S)-Xin-1-alkene-5-base) oxygen) tetrahydrochysene-2H-pyrans 146.0g, (0.670mol0 joins in reaction flask for 700ml methylene dichloride and pyridine 52.8g, reaction solution is cooled to 0 ~ 5 DEG C, add pyridinium tribromide 213.8g (0.670mol) under stirring in batches, control temperature is no more than 5 DEG C, within about 1 hour, add complete, be incubated 0-5 DEG C of stirring reaction 2 hours, it is complete that GC detects raw material reaction, 450ml saturated sodium thiosulfate cancellation reaction is dripped at temperature control 0 ~ 5 DEG C, branch vibration layer, organic phase uses 250ml saturated sodium thiosulfate solution successively, 250ml saturated aqueous common salt respectively washs once, anhydrous sodium sulfate drying, suction filtration filtrate reduced in volume is to doing to obtain oily residue.
Oily matter is joined in another reaction flask; add 1000ml tetrahydrofuran (THF) to dissolve; sodium amide 441.2g (weight in wet base is slowly added under nitrogen protection; containing dimethylbenzene); be heated to back flow reaction 5 ~ 6 hours; it is complete that GC detects raw material reaction; reaction solution is cooled to 0 DEG C, drips 680ml saturated ammonium chloride solution cancellation reaction, have a large amount of solid to separate out; 600ml ethyl acetate and 600ml water is added in mixed solution; be stirred to entirely molten, separatory, aqueous phase 500ml extraction into ethyl acetate; merge organic phase, use the saturated NaHCO of 300ml successively
3solution, 300ml saturated aqueous common salt respectively wash once, anhydrous sodium sulfate drying, suction filtration, filtrate pressurization is concentrated into dry, purified on silica obtains oily matter (6S)-6-((tetrahydrochysene-2H-pyranyl-2-base) the oxygen)-last of the ten Heavenly stems-9-alkynes 95.3g (0.400mol, total molar yield 65.8%, the GC purity of embodiment eight, nine, ten: 94.9%).
1H NMR(400MHz,CDCl
3):δ4.65-4.68(m,1H),3.87-3.94(m,1H),3.69-3.74(m,1H),3.47-3.52(m,1H),2.31-2.37(m,1H),2.24(dt,J＝2.8,7.2Hz,1H),1.92-1.95(m,1H),1.68-1.79(m,4H),1.47-1.59(m,6H),1.28-1.36(m,6H),0.89(t,J＝7.0Hz,3H)
Embodiment 11
Under nitrogen protection, trimethyl silicon based for 1-propine 78.7g (0.701mol) is dissolved in 560mL anhydrous tetrahydro furan, be cooled to-40 DEG C--50 DEG C, drip 2.5mol/L n-Butyl Lithium hexane solution 280mL, control temperature is lower than-35 DEG C, within about 30 minutes, drip and finish, be incubated-40 DEG C of stirring reactions 3 hours, drip (S)-1 dissolved with 100mL tetrahydrofuran (THF), 2-oxepane 40.0g (prepared by embodiment seven), control temperature is lower than-20 DEG C, within 30 minutes, drip and finish, be incubated-40 DEG C of stirring reactions 2 hours, it is complete that GC detects raw material reaction, drip 100mL saturated aqueous ammonium chloride cancellation reaction.Add 200mL water and 500mL ethyl acetate, separatory, organic phase with the water washing of 100mL saturated common salt once, anhydrous sodium sulfate drying, is evaporated to dry oily matter 105.7g (GC purity: 74.9%).
Above-mentioned oily matter is dissolved in 800mL ethanol, add 40gNaOH, room temperature (25 DEG C) stirring reaction 2 hours, it is complete that GC detects raw material reaction, and concentrating under reduced pressure boils off solvent, adds 500mL water and 1000mL ethyl acetate, separatory, organic phase 100mL*2 saturated common salt water washing, anhydrous sodium sulfate drying, is evaporated to dry brown oil (S)-Xin-1-alkynes-5-alcohol 73.9g (GC purity: 68.4%).
Embodiment 12
(S)-Xin-1-alkynes-5-alcohol 73.9g is dissolved in 1500ml methylene dichloride, add 3,4-dihydro-2H-pyrans (DHP) 88.3g (1.050mol) and para-methylbenzenepyridinsulfonate sulfonate (PPTs) 8.8g (0.035mol), room temperature (25 DEG C) stirring reaction 24 hours, it is complete that GC detects raw material reaction, adds the saturated NaHCO of 100mL
3with 250mL methylene dichloride, separatory, organic phase with the water washing of 100mL saturated common salt once.Anhydrous sodium sulfate drying, be evaporated to dry, purified on silica obtains oily matter (6S)-6-((tetrahydrochysene-2H-pyranyl-2-base) the oxygen)-last of the ten Heavenly stems-9-alkynes 56.2g (0.236mol, total molar yield 67.3%, the GC purity of embodiment 11,12: 93.6%).
Embodiment 13
Under nitrogen protection, by magnesium rod 31.5g (1.312moL), HgCl
22.5g (9.2mmol), iodine grain (6) add in reaction flask, and then add 300ml ether, stir, be heated to 36 DEG C of backflows, first add the initiation reaction of 5ml propargyl bromide, temperature 30-35 DEG C, 95ml propargyl bromide is dripped again at keeping temperature 0 ~ 10 DEG C, within about 1.0 hours, dropwise, continue stirring reaction 1.0 hours, keep temperature 0 ~ 10 DEG C, add (S)-1,2-oxepane 50.0g (prepared by embodiment seven), adds for about 0.5 hour, continues stirring 1.0 hours.Be cooled to-10 DEG C, 10% aqueous ammonium chloride solution 100ml is dripped at controlling 25 DEG C, within about 0.5 hour, add, finish and continue stirring 0.5 hour, filter, separatory, organic phase is respectively washed once through water (150ml), saturated aqueous common salt (150ml) successively, anhydrous sodium sulfate drying, filters, and is evaporated to dry yellow oil (S)-Xin-1-alkynes-5-alcohol 62.9g (GC purity 75.7%).
Under nitrogen protection, (S)-Xin-1-alkynes-5-alcohol 62.9g is added in reaction flask, then 400ml methylene dichloride is added, stir, be cooled to 0 DEG C, 3, 4-dihydro-2H-pyrans (DHP) 102.9g (1.223mol) and para-methylbenzenepyridinsulfonate sulfonate (PPTs) 5.1g g (0.020mol), keep temperature 20-25 DEG C of stirring reaction 24 hours, it is complete that GC detects raw material reaction, reaction solution is with adding saturated sodium bicarbonate aqueous solution (400ml × 2) washing, anhydrous sodium sulfate drying, filter, be evaporated to dry, purified on silica obtains yellow oil (6S)-6-((tetrahydrochysene-2H-pyranyl-2-base) the oxygen)-last of the ten Heavenly stems-9-alkynes 65.1g (0, 273mol, embodiment 13, 14 total molar yields 62.3%, GC purity: 96.6%).
Finally should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted the present invention, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
Claims (19)
1. the preparation method of formula I compound, is characterized in that, comprises the steps:
1) formula II compound and formula III compound or its acid salt are obtained by reacting formula IV compound under condensing agent exists;
2) formula IV compound and formula (V) compound are obtained by reacting formula I compound, and reaction formula is as follows:
Wherein, R
1, R
2be independently hydroxyl protecting group separately.
2. preparation method according to claim 1, is characterized in that, R
1, R
2independently be selected from C separately
1-8alkyl, C
1-8alcoxyl C
1-8alkyl, halogen replace C
1-8alkyl, C
3-8cycloalkyl, benzyl, C
1-8alkoxyl group substituted benzyl, THP trtrahydropyranyl ,-SiR
3r
4r
5or-C (O) R
3;
R
3, R
4, R
5independently be selected from C separately
l-8alkyl or C
3-8cycloalkyl.
3. preparation method according to claim 1, is characterized in that, R
1for benzyl, R
2for 2-THP trtrahydropyranyl.
4. the preparation method according to any one of claim 1-3, it is characterized in that, the acid of described formula III compound acid salt refers to organic acid or mineral acid, and described organic acid is selected from trifluoroacetic acid, trichoroacetic acid(TCA), methanesulfonic, trifluoromethanesulfonic acid, tosic acid or its mixture; Mineral acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, hydrofluoric acid, hydroiodic acid HI, formic acid, acetic acid or its mixture.
5. preparation method according to claim 1, is characterized in that, described condensing agent is selected from DIC, DCC, HOBT, EDC.HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or its mixture.
6. preparation method according to claim 1, it is characterized in that, step 2) in the Grignard reagent added relative to formula IV compound 0.5-10 times of molar weight, the Grignard reagent of preferred 1.0-2.0 times molar weight, described Grignard reagent preferable methyl magnesium bromide, ethylmagnesium bromide, methylmagnesium-chloride or ethylmagnesium chloride.
7. preparation method according to claim 1, is characterized in that, described formula II compound is obtained under the effect of alkali by formula (IX) compound,
Wherein R
1as claim 1 define, R
6be selected from and replace or do not replace C
1-8alkoxyl group, replacement or do not replace C
3-8cycloalkyloxy, described substituting group is selected from halogen, C
1-8alkyl, C
1-8alkoxyl group, C
3-8cycloalkyl, C
3-8cycloalkyloxy, 3-8 unit heterocyclic radical, 3-8 unit heterocyclyloxy base, C
5-10aryl, C
5-10aryloxy, 5-10 unit's heteroaryl or 5-10 unit heteroaryl oxygen base;
Described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate or its mixture.
8. preparation method according to claim 7, is characterized in that, described formula (Ⅸ) compound is obtained under the effect of alkali by formula (VIII) compound,
Wherein R
1as claim 1 define, R
6as claim 7 define; Described alkali is organic bases or mineral alkali, described organic bases is selected from Trimethylamine 99, triethylamine, pyridine, piperidines, morpholine or its mixture, and described mineral alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium-acetate or its mixture.
9. preparation method according to claim 8, is characterized in that, the preparation method of described formula (VIII) compound is as follows:
Wherein R
6as claim 7 define, preferred methoxyl group, oxyethyl group; X is halogen, preferred bromine.
10. preparation method according to claim 1, is characterized in that, be that described formula (V) compound prepared by raw material with formula (Ⅺ) compound, preparation method is as follows:
Or,
Or,
Wherein R
2, R
3, R
4, R
5as claim 1 define, X is halogen.
11. preparation methods according to claim 10, is characterized in that, the preparation method of described formula (Ⅺ) compound is as follows:
The preparation method of 12. 1 kinds of formula (V) compounds, is characterized in that, comprise the steps:
Wherein R
2as claim 1 define; X is halogen.
The preparation method of 13. formula according to claim 12 (V) compounds, is characterized in that, work as R
2when being selected from 2-THP trtrahydropyranyl, it comprises the steps:
The preparation method of 14. 1 kinds of formula (V) compounds, is characterized in that, comprise the steps:
Wherein R
2, R
3, R
4, R
5as claim 1 define.
The preparation method of 15. formula according to claim 14 (V) compounds, is characterized in that, work as R
2when being selected from 2-THP trtrahydropyranyl, it comprises the steps:
The preparation method of 16. 1 kinds of formula (V) compounds, is characterized in that, comprise the steps:
Wherein R
2as claim 1 define; X is halogen.
The preparation method of 17. formula according to claim 16 (V) compounds, is characterized in that, work as R
2when being selected from 2-THP trtrahydropyranyl, it comprises the steps:
18. formula IV compounds:
Wherein, R
1be selected from C
1-8alkyl, C
1-8alcoxyl C
1-8alkyl, halogen replace C
1-8alkyl, C
3-8cycloalkyl, benzyl, C
1-8alkoxyl group substituted benzyl, THP trtrahydropyranyl ,-SiR
3r
4r
5,-C (O) R
3; R
3, R
4, R
5independently be selected from C separately
l-8alkyl or C
3-8cycloalkyl.
19. formula IV compounds according to claim 18, is characterized in that, R
1be selected from methyl, ethyl, the tertiary butyl or benzyl.
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| CN111116419B (en) | 2022-03-29 |
| CN104892555B (en) | 2019-03-08 |
| CN111116419A (en) | 2020-05-08 |
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