CN108675943A - The preparation method of one planting sand library Ba Qu key intermediates - Google Patents
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Abstract
The invention discloses the synthesis preparation methods of a planting sand library Ba Qu key intermediates N [(1R) 2 [1,1 ' biphenyl] 4 base 1 (hydroxymethyl) ethyl] t-butyl carbamate.The preparation method is using 4 biphenylcarboxaldehydes and hydantoins as starting material, and by being condensed and hydrolyze " one kettle way " reaction, esterification, asymmetry turns aminating reaction, Boc is protected and reduction reaction is synthetically prepared target product.The preparation method has the characteristics that reaction raw materials are easy to get, route is short, reaction stereoselectivity height, mild condition, technological operation are easy, suitable industrialized production.
Description
Technical field
The present invention relates to the synthesis preparation methods of a planting sand library Ba Qu key intermediates, belong to pharmaceutical synthesis field.
Background technology
Sha Kuba song Valsartan sodium（Sacubitril Valsartan Sodium）It is global chronic heart failure in the latest 20 years
The breakthrough innovation drug of therapy field can inhibit enkephalinase and block AT1 receptors simultaneously（1 type of Angiotensin II by
Body）.The drug is by Novartis limited liability company of Switzerland（Novartis Pharma Schweiz AG）Exploitation, in 2015
July 7 was approved by the FDA in the United States listing, trade name：Entresto®.Europe is recommended by the European's medication committee on the 24th of September in 2015
Alliance ratifies it and treats heart failure in Europe listing.China CFDA ratifies its listing within 2017, and trade name promise is glad appropriate®.Sha Kuba is bent
Valsartan sodium piece listing specification and dosage form are：50mg, 100mg, 200mg tablet.Sha Kuba songs Valsartan Sodium chemistry entitled ten
Eight sodium six (4- [(1S, 3R) -1- ([1,1 '-xenyls) -4- ylmethyls) -4- ethyoxyl -3- methyl -4- oxos butyl] ammonia
Base } -4- ketobutyric acids) six (N- valeryls -N-{[2′-(1HTetrazole -5- bases) biphenyl -4- bases] methyl }-Valine) -
Water (1/15), chemical structural formula is as follows：
。
Sha Kuba is bent（Sacubitril）For enkephalinase inhibitor, main function is the natriuresis reduced in atrium and brain
Peptide reduces blood volume, and generates antihypertensive effect.Valsartan is angiotensinⅡ（AT1）Receptor antagonist, it selectively makees
For AT1 receptor subtypes, the combination of Ang II and AT1 receptors are blocked（The effect of its specific antagonist AT1 receptors is more than AT2 receptors
About 20,000 times）, to inhibit the release of vessel retraction and aldosterone, generate antihypertensive effect.The two combines, and is clinically used to penetrate
The chronic heart failure that blood fraction reduces（II-IV grade of NYHA, LVEF≤40%）Adult patient, reduce cardiovascular death and
The risk that heart failure is hospitalized.Sha Kuba song Valsartan sodium piece can replace angiotensin converting enzyme inhibitors（ACEI）Or blood vessel
Angiotensin Ⅱ receptor antagonist（ARB）, with other heart failure therapy drugs（Such as：Beta-blockers, diuretics and salted hide
Matter hormone antagonist）It shares.
The synthetic method of Sha Kuba song Valsartan sodium has many document reports.Yuan Yan companies have applied for a series of husky libraries
The preparation method of Ba Qu, Sha Kuba song Valsartan sodium and its intermediate, wherein most representative preparation method（PCT Patent,
WO2014/032627）Disclose following synthetic route（1）：
。
In said synthesis route, N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] carbamic acid
The tert-butyl ester（Compound I）It is the key intermediate for synthesizing Sha Kuba song Valsartan sodium.About the correlative study of the key intermediate,
A variety of preparation methods are developed, chemical structural formula is as follows：
。
Novartis limited liability company of Yuan Yan Switzerland reporting（PCT Patent, WO2010/081410;It is Chinese special
Profit, CN101774941A and CN102482202B）, the raceme of N- acetyl phenyl alanines, then chiral fractionation are synthesized first
(R)-N- acetyl phenyl alanines are prepared, which can be prepared N- [(1R)-subsequently through series of chemical
2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate.Synthetic route is as follows：
。
This method uses the heated decarboxylic reaction of malonate derivative, and the racemization of N- acetyl phenyl alanines is prepared
Body is split using chiral resolving agent (S) -1- phenyl ethylamines, (R)-N- acetyl phenyl alanines is prepared.The technique originates
Raw material malonate derivative is not easy to prepare, and resolution reaction yield is low, resolution process usually prevent the product of another configuration from
Utilize, or cannot completely racemization be used again, cause the intermediate feed cost increase, be not suitable for industrialized production.
The said firm reports again（PCT Patent, WO2011/035569；Chinese patent, CN102639486A）With 4- biphenyl first
Aldehyde, N- acetyl-glycines are raw material through condensation reaction, hydrolysis, most prepare chiral N- acetylbenzenes through catalytic hydrogenation afterwards
Alanine.Synthetic route is as follows：
。
This method preparation route is shorter, in catalytic hydrogenation step, use transition metal and chiral ligand for catalyst not
Symmetric hydrogenation reacts, and the method for reference is the C.2 part content in WO2009/090251, using ruthenium catalyst with
The catalytic asymmetric hydrogenation of Mandyphos chiral ligands prepares chiral N- acetyl phenyl alanines.The catalysts
It is of high cost, and the data such as the optical purity of product prepared by this method and each step intermediate yield are not disclosed.
In addition there are documents（PCT Patent, WO2013/026773）It reports with 4- biphenylcarboxaldehydes and the sweet ammonia of N- benzoyls
Acid is that in the presence of aceticanhydride intermediate is prepared again through methanol open loop, gained intermediate is through ruthenium catalyst and chirality list in raw material
Phosphorus ligand（S-PiPhos）It is catalyzed asymmetric hydrogenation and restores double bond, obtain ＞ 99%eeEnantioselectivity intermediate, then through urging
After changing hydro-reduction and Boc protections, N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] amino first is obtained
Tert-butyl acrylate.In addition, PCT Patent（WO2015/024991）Also similar method is reported.
The starting material N- benzoylglycine higher prices of above method, asymmetric hydrogenation restore double bond reaction and use
Expensive ruthenium catalyst and chiral monophosphorous ligand are subsequently debenzylation catalyst using palladium carbon, and catalyst amount is larger,
Cost of material is higher.Synthetic route is as follows：
。
Later stage Yuan Yan, Switzerland's Novartis limited liability company reported（PCT Patent, WO2014/032627）Joined by 4- bromines
Benzene is that starting material prepares grignard reagent, then is prepared with optical activation through grignard reaction with (S)-epoxychloropropane
Chloro alcohol intermediate, the intermediate is in diethyl azodiformate（DEAD）In the presence of, Mitsunobu occurs with succimide
Reaction, is prepared configuration reversal intermediate, then intermediate is prepared through hydrolysis, finally anti-with di-tert-butyl dicarbonate
N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate should be prepared.
This method is used introduces chiral centre with chiral source raw material, avoids fractionation and refines, but this method is anti-using format
It should need control cryogenic conditions, follow-up Mitsunobu reactions, reaction dissolvent that need to be dehydrated degassing process, DEAD is quick to light, heat and vibrations
Sense, when heating can high-explosive, influence production safety.In addition, the step byproduct of reaction is not readily separated, it is pure to influence intermediate product
Degree.Synthetic route is shown in said synthesis route（1）.
Chinese patent（CN105198775B）It reports with 4- biphenylcarboxaldehydes, 2- acetamidos -2- (dimethoxy phosphonos
Base) methyl acetate be raw material, under the action of DBU, after condensation reaction, then through ruthenium catalyst and chiral diphosphine ligand（(Rc,
Sp)-Duanphos）Be catalyzed asymmetric hydrogenation restore double bond, then pass through several steps it is similar be obtained by the reaction N- [(1R) -2- [1,
1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate.Synthetic route is as follows：
。
This method raw material 2- acetamidos -2- (dimethoxy phosphono) methyl acetate is not easy to, and intermediate Part is adopted
It is carried out with chiral diphosphine ligand using ruthenium catalyst with asymmetric hydrogenation, follow-up hydrazinolysis reacts deacetylate, using easy
The hydrazine hydrate solution of combustion, influences industrial operation.
Chinese patent（CN105884656B）It reports using benzyl magnesium bromide, Methyl oxatyl chloride as raw material, by contracting
It closes, after phenyl ring bromo, then be coupled with phenyl boric acid, obtains xenyl pyruvate.Again in glucose/NADP+/ ketoreductase
In the presence of CGKR2/GDH, after reduction amination, the reduction of Boc protection and ester group is carried out, obtains N- [(1R) -2- [1,1 '-connection
Benzene] -4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate.
This method mainly uses the reduction amination of reduced coenzyme that chiral amine intermediates are prepared, and this method is different
In the above-mentioned asymmetric hydrogenation method using ruthenium catalyst and chiral phosphine ligand, it is solvent which, which needs a large amount of water,
The concentration of substrate is low, and the efficiency of industrialization is low.Synthetic route is as follows：
。
In addition, the coupling reaction that this method is catalyzed using the grignard reaction for needing low temperature control, stannous chloride, reaction yield are inclined
It is low, while a large amount of cupric bisulfate waste liquors generate, and to the bromo-reaction of aromatic rings, have been easy more bromos and bromo regioisomers are miscellaneous
The generation of matter, such impurity are just difficult to purify removal once generating.
Invention content
The purpose of the present invention is to provide a planting sand library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -
1- (hydroxymethyl) ethyl] t-butyl carbamate preparation method, it is intended to overcome present in method made above insufficient.
The present invention provides a planting sand library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxyl first
Base) ethyl] t-butyl carbamate preparation method, chemical structural formula is as shown in following formula I：
。
[(1R) -2- [1,1 '-the biphenyl] -4- bases-of Sha Kuba songs key intermediate N- shown in Formulas I provided by the present invention
1- (hydroxymethyl) ethyl] t-butyl carbamate preparation method, preparation methods steps are as follows：
Step 1：4- biphenylcarboxaldehydes and hydantoins hydrolyze after condensation reaction in the presence of base, in obtaining shown in Formula II
Mesosome II；
Step 2：Intermediate III shown in formula III is prepared through esterification in intermediate II shown in Formula II；
Step 3：Intermediate III shown in formula III turns aminating reaction through asymmetry, obtains in the presence of chiral base catalyst
Intermediate compound IV shown in formula IV；
Step 4：Intermediate compound IV shown in formula IV, is protected through Boc, obtains intermediate V shown in Formula V；
Step 5：Sha Kuba songs key intermediate N- shown in Formulas I is prepared through reduction reaction in intermediate V shown in Formula V
[(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate.
The chemical constitution and synthetic route of intermediate shown in above-described Formulas I, Formula II, formula III, formula IV and Formula V
As follows：
。
Chiral catalyst described in step 3 includes following several：
。
In above-mentioned route steps 1, the present invention uses glycolylurea method（Hydantoins）To prepare in 2-ketoacid structure
Mesosome II.Preparation method research about 2-ketoacid is more, and synthesizes 2-ketoacid by glycolylurea method and be reported very early, this method
Because its reaction condition is simple, by-product is few, and cost of material is low and by numerous studies.Billek etc.（Monatshefte für
Chemie, 1961, 92, 335-342）It reports with parahydroxyben-zaldehyde and hydantoins（Glycolylurea）For raw material, deposited in piperidines
Benzal glycolylurea intermediate is prepared through condensation reaction lower, finally hydrolyzes and is prepared to hydroxyl under sodium hydroxide effect
Phenylpyruvic acid, the route total moles yield about 50%, reaction route is as follows：
。
This method reaction mechanism：The generation Knoevenagel condensation reactions of first step parahydroxyben-zaldehyde and hydantoins,
Under the catalysis of piperidines alkali, active α-H atom on the methylene of hydantoins, slough in the presence of alkali to be formed carbon bear from
Son occurs to be condensed and is dehydrated into double bond, obtains benzal glycolylurea intermediate with aldehyde.Second step benzal glycolylurea intermediate is in alkali
Effect issues raw hydrolysis, and two C-N keys are broken, and obtain Single-chip microcomputer.The first step in preparation process,
The alkali being often used is included in ethanol amine, piperidines, ammonium acetate etc..
1985, Alain Schouteeten etc.（US4518800）It reports using benzaldehyde and hydantoins as raw material,
The suspension of benzal glycolylurea intermediate is prepared under ethanol amine effect, the intermediate is without isolation in the effect of lye
Under, Phenylpyruvic Acid Sodium Salt is prepared in high yield.This method provides can preparation of industrialization 2-ketoacid and its derivative skill
Art, the route total moles yield about 99%（Product recovery rate counts in mother liquor）, reaction route is as follows：
。
1999, Jan Raap etc.（Eur. J. Org. Chem., 1999, 10, 2609-2621）Equally report
Using benzaldehyde and hydantoins as raw material, method that Phenylpyruvic Acid Sodium Salt is prepared in the presence of sodium acetate.This method is preparing Asia
In the separation process of benzyl glycolylurea intermediate, the raw material benzaldehyde of unreacted complete 13% is recycled, in Sodium.beta.-phenylpyruvate
During salt preparative separation, only carbon dioxide and ammonia generate, and no other organic by-products generate, and products obtained therefrom is not necessarily into one
Step separation, two step total moles yields 53.2%, reaction route is as follows：
。
There are problem, most of method is both needed to complete step by step the above published technical method, especially needs to isolate and purify
Benzal glycolylurea intermediate, technological operation is cumbersome, eventually leads to and prepares 2-ketoacid and its derivative total recovery is relatively low, each step is total
For molar yield about 50% or so, Some routes, which need to isolate and purify mother liquor, could improve total recovery.
In order to solve the above problem, the present invention has been attempted using a variety of different alkali, the dosage of change alkali and differential responses
The parameters such as temperature.Inventor find it is optimized after technological parameter, intermediate shown in " one kettle way " formula II can be passed through
II, for gained intermediate without isolating and purifying, i.e. 2-ketoacid product is prepared in high yield.Products obtained therefrom purity is high, almost without
By-product and impurity generate.Main research is as follows：
It can be seen from the above result that ethanol amine, piperidines or ammonium acetate is used catalyzing and condensing can be reacted well for alkali, wherein with
The catalytic effect of ethanol amine is best.According to reaction mechanism and general organic synthesis common sense it is recognised that in addition to above 3 kinds of alkali,
It should may be used to be catalyzed the condensation reaction using other organic bases or inorganic base.
Intermediate III shown in step 3 formula III turns aminating reaction in the presence of chiral base catalyst through asymmetry,
Obtain intermediate compound IV shown in formula IV.
A-amino acid with optical activation is one of substance mostly important in organism and organic synthesis, α-in human body
Amino acid be synthesized by 2-ketoacid turn aminating reaction realization.Using the asymmetry of chemical catalysis turn aminating reaction by
Numerous studies and report, wherein it is to use pyridoxal and its chiral derivatives containing pyridine ring structure to study more, as
Asymmetry turns the catalyst of aminating reaction, the i.e. analog of vitamin B6.But the type chiral catalyst, need multi-step and
Harsh reaction condition synthesizes, and causes the catalyst preparation cost higher, and be not easily recycled utilizations, while use the type is urged
The asymmetry of agent turns the chiralα-aminoacid and its derivative of aminating reaction preparation, and optical purity is difficult to reach industrial applications
Requirement.
Soloshonok etc.（Tetrahedron Letters, 1994, 35, 5063-5064）Report, with
Cinchonidine is chiral catalyst, using beta-ketoester and benzylamine as raw material, turns aminating reaction through asymmetry and obtains (R)-β-
Fluoroalkyl-beta-amino acids, yield 67 ~ 89%, buteeValue only up to 36%.Reaction is as follows：
。
Shi etc.（J. Am. Chem. Soc., 2011, 133, 12914-12917）It reports and is derived with quinine
Object is chiral catalyst, using alpha-keto ester and o-chlorine benzylamine as raw material, through turning aminating reaction, obtains α-aminoacidesters in high yield.
The conversion ratio of reaction is up to 100%, and the optical purity of product is up to 92%ee.Reaction is as follows：
。
The reaction mechanism may be：Ketone carbonyl in o-chlorine benzylamine and α -one esters is condensed, and forms imine intermediate, among this
There are tautomerisms for body, and under the catalysis of chiral cinchona alkaloid-derived ligands, the methene proton of benzylamine is sloughed and chiral base base junction
It closes, ketimine intermediate electronics transfer forms delocalization intermediate, and the intermediate is under the chiral centre induction of chiral base, with chirality
Proton translocation occurs for the hydrogen that alkali combines, and finally hydrolysis obtains chiralα-aminoacid ester.Chiral base catalyst used in this method
As follows：
。
The present invention uses asymmetry and turns aminating reaction in step 3, is with alpha-keto ester intermediate III and o-chlorine benzylamine
Raw material turns aminating reaction in the presence of chiral base catalyst through asymmetry, obtains chiralα-aminoacid ester intermediate compound IV.It should
Step turns aminating reaction and has selected chiral base catalyst C-1, C-2, C-3 and C-4, and to the progress such as reaction dissolvent and catalyst amount
In-depth study.Main research is summarized as follows：
The chemical constitution of above-described catalyst C-1, C-2, C-3 and C-4 are as follows：
；。
Result of study shows, catalyst C-1, C-2, C-3 and C-4 can the asymmetry of catalytic step 3 well turn ammonification
Reaction, wherein with the best results of catalyst C-1.According to the common sense of reaction mechanism and organic synthesis, can speculate divided by
Upper 4 kinds of chiral catalysts, should can be used for being catalyzed the asymmetry and turn ammonia using the chiral base molecule of other similar structures
Change reaction.Since the catalyst of the above structure type does not dissolve in n-hexane, this can be made by the way that n-hexane is added in post-processing
Class catalyst forms Precipitation, recycles catalyst after filtering, can reach the purpose of recycling.
According to the common sense of reaction mechanism and organic synthesis, it can speculate in addition to o-chlorine benzylamine, adjacent fluorin benzyl amine, to nitro
Unsubstituted benzylamine on the alpha substituted benzylamines such as benzylamine or phenyl ring, it should which the asymmetry that can also be used for step 3 turns aminating reaction.
Specifically, [(1R) -2- [1, the 1 '-connection of Sha Kuba songs key intermediate N- shown in Formulas I provided by the present invention
Benzene] -4- bases -1- (hydroxymethyl) ethyl] synthesis preparation method of t-butyl carbamate can realize in accordance with the following steps：
Step 1：Under 50 ~ 70 DEG C, stirring, a certain amount of hydantoins, ethanol amine or piperidines are added in a certain amount of water,
After being warming up to reflux, the ethanol solution of 4- biphenylcarboxaldehydes is added dropwise, after being added dropwise, continues to maintain the reflux for reacting, TLC detections are anti-
It answers, until the raw material point of 4- biphenylcarboxaldehydes disappears；20% sodium hydrate aqueous solution is added, continues back flow reaction 3 ~ 6 hours；It will
Reaction solution is cooled to 5 DEG C hereinafter, with concentrated hydrochloric acid adjusting pH to 4 ~ 5, and after partial solvent is evaporated off, solid filtering will be precipitated, dry, obtains
To intermediate II shown in Formula II.The molar ratio of the 4- biphenylcarboxaldehydes, hydantoins and organic base is 1:1:0.1~
0.5。
Step 1 can also be realized in accordance with the following steps：A certain amount of 4- biphenylcarboxaldehydes, hydantoins and ammonium acetate are added
Into a certain amount of acetic acid, it is warming up to back flow reaction, TLC detection reactions are evaporated off molten until the raw material point of 4- biphenylcarboxaldehydes disappears
After agent, ethyl alcohol and 20% sodium hydroxide solution are added, continues back flow reaction 3 ~ 6 hours；By reaction solution be cooled to 5 DEG C hereinafter, with
Concentrated hydrochloric acid tune pH to 4 ~ 5 removes solvent under reduced pressure, and residue is dissolved with a certain amount of ethyl acetate, after washing, organic phase drying,
Filtering, it is dry after filtrate concentration, obtain intermediate II shown in Formula II.4- biphenylcarboxaldehydes, hydantoins and the ammonium acetate
Molar ratio be 1:1:0.5~2.
Step 2：At room temperature, intermediate II and acid catalyst shown in a certain amount of Formula II are added to a certain amount of anhydrous
In ethyl alcohol, stirring is opened, is warming up to back flow reaction, TLC detection reactions are cooled to room until the raw material point of intermediate II disappears
Temperature, after removing solvent under reduced pressure, residue is dissolved with ethyl acetate, and after washing, drying after solvent is evaporated off in organic phase drying, filtering,
Obtain intermediate III shown in formula III.
One kind in the concentrated sulfuric acid, p-methyl benzenesulfonic acid, trifluoromethane sulfonic acid may be selected in acid catalyst described in above step 2
Or a variety of mixtures.According to organic synthesis mechanism it is found that other organic acids, inorganic acid, solid Lewis acid, acid ion are handed over
Change resin etc. can also catalytic step 2 esterification.
Step 3：Under room temperature and nitrogen protection, in a certain amount of dehydrated organic solvent A, it is added with stirring a certain amount of
Intermediate III shown in formula III and a certain amount of o-chlorine benzylamine are warming up to back flow reaction, TLC detection reactions, until intermediate
The raw material point of III disappears；A certain amount of chiral organic alkali catalyst is added, is reacted 18 ~ 36 hours under 50 DEG C to reflux temperature
Afterwards, remove solvent under reduced pressure, residue is added a certain amount of ethyl alcohol, control temperature at 5 DEG C hereinafter, a certain amount of 1N hydrochloric acid is added,
And 5 DEG C it is stirred below reaction 1 ~ 5 hour after, with solid sodium bicarbonate adjust pH to 8, remove solvent under reduced pressure, residue is used again
Dichloromethane dissolves, washing, organic phase drying, and filtering is dry after solvent is evaporated off in filtrate decompression, obtains intermediate shown in formula IV
Body IV.
Organic solvent A described in step 3 may be selected in toluene, benzene, chloroform, dichloromethane, methanol, ethyl alcohol, acetonitrile
It is a kind of.
One kind in catalyst C-1, C-2, C-3, C-4 may be selected in chiral organic alkali catalyst described in step 3.
Intermediate III, o-chlorine benzylamine shown in formula III described in step 3 and chiral feeding intake for organic alkali catalyst are rubbed
You are than being 1:1:0.05~0.15.
Step 4：At room temperature, in a certain amount of dichloromethane, intermediate compound IV, two carbon shown in a certain amount of formula IV is added
The 4-dimethylaminopyridine of sour di tert butyl carbonate, triethylamine and catalytic amount, is stirred to react, TLC detection reactions, until intermediate compound IV
Raw material point disappears, dry after organic phase washing, and filtering is dry after solvent is evaporated off in filtrate decompression, obtains intermediate shown in Formula V
V。
The molar ratio of intermediate compound IV, triethylamine, di-tert-butyl dicarbonate described in step 4 is 1:1:1.0~1.5.
Step 5：At room temperature, in a certain amount of tetrahydrofuran, stirring is opened, intermediate V shown in Formula V is added, in batches
It is secondary that a certain amount of Lithium Aluminium Hydride is added, it is warming up to 50 DEG C and is reacted to reflux temperature, TLC detections are reacted, until the raw material of intermediate V
Point disappears, and a certain amount of water is added, and stirs 30 minutes, after removing organic solvent under reduced pressure, a certain amount of ethyl acetate is added, organic
Dry after mutually washing, filtering is dry after solvent is evaporated off in filtrate decompression, obtains intermediate compound I shown in Formulas I.
[(1R) -2- [1,1 '-the biphenyl] -4- bases-of Sha Kuba songs key intermediate N- shown in Formulas I provided by the present invention
1- (hydroxymethyl) ethyl] t-butyl carbamate synthesis preparation method, novelty is embodied in the following：
（1）Use the 4- biphenylcarboxaldehydes being easy to get in the market with hydantoins for raw material, through condensation and hydrolysis, " one kettle way " system
It is standby to obtain 2-ketoacid intermediate II, do not need that the harsh reaction condition such as anhydrous and oxygen-free, industrial operation be simple, high income；
（2）Aminating reaction is turned using the asymmetry for the chiral base catalysis being easy to get, (R)-amino ketone ester intermediate compound IV is prepared, by ketone carbonyl
One step of base is converted into chiral amino, and the reaction condition of this method is mild, product stereoselectivity and high income, and catalyst can return
Receive cycling and reutilization；
（3）In entire synthesis technology, the reaction condition of no special harshness, technology stability is good, controllability is high, is suitble to industrialization
Production.
In short, [(the 1R) -2- [1,1 '-biphenyl]-of Sha Kuba songs key intermediate N- shown in Formulas I provided by the present invention
4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate synthesis preparation method, have raw material is easy to get, route is shorter, reaction
Mild condition, stereoselectivity and high income, the features such as technological operation is easy, are suitble to industrialized production.
Specific implementation mode
Following exemplary embodiments are used for illustrating the present invention, the letter that technical staff in the art is the present invention
Single replacement or improvement etc. belong within the technical solution that the present invention is protected.
Starting material in the embodiment of the present invention is known, and can be bought on the market, or can be according to ability
Known method synthesizes in domain.
Embodiment 1：Intermediate II is synthetically prepared
In reaction bulb, 500ml water is added, after being warming up to 60 DEG C, hydantoins is sequentially added under stirring（100.1g,
1.0mol）And ethanol amine（12.2g, 0.2mol）, after being warming up to reflux, 4- biphenylcarboxaldehydes are added dropwise（182.2g, 1.0mol）'s
Ethyl alcohol（500ml）Solution after being added dropwise, continues to maintain the reflux for reacting, TLC detection reactions, until the raw material of 4- biphenylcarboxaldehydes
Point disappears；Add 20% sodium hydrate aqueous solution（200ml）, continue back flow reaction 4 hours；By reaction solution be cooled to 5 DEG C with
Under, pH to 4 ~ 5 is adjusted with concentrated hydrochloric acid, removes about 600ml solvents under reduced pressure, solid filtering will be precipitated, it is dry, it obtains shown in Formula II
Intermediate II（229.6g, 0.956mol）, molar yield 95.6%.
Embodiment 2：Intermediate II is synthetically prepared
In reaction bulb, 500ml water is added, after being warming up to 50 DEG C, hydantoins is sequentially added under stirring（100.1g,
1.0mol）And ethanol amine（30.6g, 0.5mol）, after being warming up to reflux, 4- biphenylcarboxaldehydes are added dropwise（182.2g, 1.0mol）'s
Ethyl alcohol（500ml）Solution after being added dropwise, continues to maintain the reflux for reacting, TLC detection reactions, until the raw material of 4- biphenylcarboxaldehydes
Point disappears；Add 20% sodium hydrate aqueous solution（200ml）, continue back flow reaction 5 hours；By reaction solution be cooled to 5 DEG C with
Under, pH to 4 ~ 5 is adjusted with concentrated hydrochloric acid, removes about 600ml solvents under reduced pressure, solid filtering will be precipitated, it is dry, it obtains shown in Formula II
Intermediate II（231.1 g, 0.962mol）, molar yield 96.2%.
Embodiment 3：Intermediate II is synthetically prepared
In reaction bulb, by 4- biphenylcarboxaldehydes（182.2g, 1.0mol）, hydantoins（100.1g, 1.0mol）And ammonium acetate
（77.1g, 1.0mol）It is added in 800ml acetic acid, is warming up to back flow reaction, TLC detection reactions, up to 4- biphenylcarboxaldehydes
Raw material point disappears, and after removing solvent under reduced pressure, adds 500ml ethyl alcohol and 20% sodium hydroxide solution（200ml）, continue to stir back
Stream reaction 6 hours；Reaction solution is cooled to 5 DEG C hereinafter, with concentrated hydrochloric acid tune pH to 4 ~ 5, removes solvent, residue 1L second under reduced pressure
Acetoacetic ester dissolves, and uses water（300ml×2）After washing, organic phase drying, filtering is dry after filtrate concentration, obtains shown in Formula II
Intermediate II（211.2g, 0.879mol）, molar yield 87.9%.
Embodiment 4：Intermediate III is synthetically prepared
At room temperature, in reaction bulb, intermediate II shown in 1L absolute ethyl alcohols and Formula II is added（240.2g, 1.0mol）, then add
Enter the 20ml concentrated sulfuric acids, open stirring, is warming up to back flow reaction, TLC detection reactions, until the raw material point of intermediate II disappears, it is cold
But to room temperature, after removing solvent under reduced pressure, residue 1L ethyl acetate dissolves, and uses water（300ml×2）It is organic relevant after washing
Dry, filtering removes drying after solvent under reduced pressure, obtains intermediate III shown in formula III（259.8g, 0.968mol）, mole receipts
Rate is 96.8%.
Embodiment 5：Intermediate compound IV is synthetically prepared
Under room temperature and nitrogen protection, the toluene of 2L dryings is added in reaction bulb, opens stirring, in being added shown in formula III
Mesosome III（268.3g, 1.0mol）And o-chlorine benzylamine（141.6g, 1.0mol）, it is warming up to back flow reaction 12 hours, TLC inspections
It surveys, the raw material point of intermediate III disappears substantially；70 DEG C are cooled to, catalyst C-1 is added（29.4g, 0.1mol）, maintain 70
DEG C reaction 24 hours after, be cooled to room temperature, be added 2L n-hexanes, have Precipitation, catalyst be recovered by filtration；Filtrate decompression is evaporated off
After solvent, 1.5L ethyl alcohol is added in residue, and control temperature is at 5 DEG C hereinafter, 1N hydrochloric acid is added（1.5L）, and maintain to stir at 5 DEG C
After mixing reaction 3 hours, pH to 8 is adjusted with solid sodium bicarbonate, removes solvent, residue dichloromethane under reduced pressure（1.5L）It is molten
Solution, uses water（400ml×2）After washing, organic phase drying, filtering is dry after solvent is evaporated off in filtrate decompression, obtains shown in formula IV
Intermediate compound IV（203.6g, 0.756mol）, molar yield 75.6%, chiral HPLC methods detection producteeValue is 83%.
Embodiment 6：Intermediate compound IV is synthetically prepared
Under room temperature and nitrogen protection, the toluene of 2L dryings is added in reaction bulb, opens stirring, in being added shown in formula III
Mesosome III（268.3g, 1.0mol）And o-chlorine benzylamine（141.6g, 1.0mol）, it is warming up to back flow reaction 18 hours, TLC inspections
It surveys, the raw material point of intermediate III disappears substantially；90 DEG C are cooled to, catalyst C-3 is added（33.8g, 0.1mol）, maintain 90
DEG C reaction 18 hours after, be cooled to room temperature, be added 2L n-hexanes, have Precipitation, catalyst be recovered by filtration；Filtrate decompression is evaporated off
1.5L ethyl alcohol is added in solvent, residue, and control temperature is at 5 DEG C hereinafter, 1N hydrochloric acid is added（1.5L）, and maintain to stir at 5 DEG C
After reaction 5 hours, pH to 8 is adjusted with solid sodium bicarbonate, removes solvent, residue dichloromethane under reduced pressure（1.5L）Dissolving,
Use water（400ml×2）After washing, organic phase drying, filtering is dry after removing solvent under reduced pressure, obtains intermediate shown in formula IV
IV（161.8g, 0.601mol）, molar yield 60.1%, chiral HPLC methods detection producteeValue is 53%.
Embodiment 7：Intermediate compound IV is synthetically prepared
Under room temperature and nitrogen protection, the chloroform of 1.5L dryings is added in reaction bulb, opens stirring, is added shown in formula III
Intermediate III（268.3g, 1.0mol）And o-chlorine benzylamine（141.6g, 1.0mol）, it is warming up to back flow reaction 24 hours, TLC
Detection, the raw material point of intermediate III disappear substantially；50 DEG C are cooled to, catalyst C-1 is added（29.4g, 0.1mol）, maintain
It after 50 DEG C are reacted 18 hours, is cooled to room temperature, 2L n-hexanes is added, has Precipitation, catalyst is recovered by filtration；Filtrate decompression is steamed
Except solvent, 1.5L ethyl alcohol is added in residue, and control temperature is at 5 DEG C hereinafter, 1N hydrochloric acid is added（1.5L）, and maintain to stir at 5 DEG C
After mixing reaction 5 hours, pH to 8 is adjusted with solid sodium bicarbonate, removes solvent, residue dichloromethane under reduced pressure（1.5L）It is molten
Solution, uses water（400ml×2）After washing, organic phase drying, filtering is dry after removing solvent under reduced pressure, in obtaining shown in formula IV
Mesosome IV（140.8g, 0.523mol）, molar yield 52.3%, chiral HPLC methods detection producteeValue is 63%.
Embodiment 8：Intermediate compound IV is synthetically prepared
Under room temperature and nitrogen protection, the methanol of 1.6L dryings is added in reaction bulb, opens stirring, is added shown in formula III
Intermediate III（268.3g, 1.0mol）And o-chlorine benzylamine（141.6g, 1.0mol）, it is warming up to back flow reaction 20 hours, TLC
Detection, the raw material point of intermediate III disappear substantially；50 DEG C are cooled to, catalyst C-1 is added（29.4g, 0.1mol）, reheat
It to back flow reaction 36 hours, removes solvent under reduced pressure, is cooled to room temperature, residue 1.5L dichloromethane dissolves, and 1.5L is added
N-hexane has Precipitation, and catalyst is recovered by filtration；Solvent is evaporated off in filtrate decompression, and 1.5L ethyl alcohol is added in residue, controls temperature
At 5 DEG C hereinafter, 1N hydrochloric acid is added（1.5L）, and maintain after being stirred to react 5 hours at 5 DEG C, adjust pH with solid sodium bicarbonate
To 8, solvent, residue dichloromethane are removed under reduced pressure（1.5L）Dissolving, uses water（400ml×2）After washing, organic phase drying,
Filtering, it is dry after removing solvent under reduced pressure, obtain intermediate compound IV shown in formula IV（178.3g, 0.662mol）, molar yield is
66.2%, chiral HPLC methods detection producteeValue is 76%.
Embodiment 9：Intermediate compound IV is synthetically prepared
Under room temperature and nitrogen protection, the acetonitrile of 1.6L dryings is added in reaction bulb, opens stirring, is added shown in formula III
Intermediate III（268.3g, 1.0mol）And o-chlorine benzylamine（141.6g, 1.0mol）, it is warming up to back flow reaction 24 hours, TLC
Detection, the raw material point of intermediate III disappear substantially；50 DEG C are cooled to, catalyst C-1 is added（29.4g, 0.1mol）, reheat
It to back flow reaction 18 hours, removes solvent under reduced pressure, is cooled to room temperature, residue 1.5L dichloromethane dissolves, and 1.5L is added
N-hexane has Precipitation, and catalyst is recovered by filtration；Solvent is evaporated off in filtrate decompression, and 1.5L ethyl alcohol is added in residue, controls temperature
At 5 DEG C hereinafter, 1N hydrochloric acid is added（1.5L）, and maintain after being stirred to react 5 hours at 5 DEG C, adjust pH with solid sodium bicarbonate
To 8, solvent, residue dichloromethane are removed under reduced pressure（1.5L）Dissolving, uses water（400ml×2）After washing, organic phase drying,
Filtering, it is dry after removing solvent under reduced pressure, obtain intermediate compound IV shown in formula IV（252.1g, 0.936mol）, molar yield is
93.6%, chiral HPLC methods detection producteeValue is 96%.
Embodiment 10：Intermediate compound IV is synthetically prepared
Under room temperature and nitrogen protection, the acetonitrile of 1.6L dryings is added in reaction bulb, opens stirring, is added shown in formula III
Intermediate III（268.3g, 1.0mol）And o-chlorine benzylamine（141.6g, 1.0mol）, it is warming up to back flow reaction 24 hours, TLC
Detection, the raw material point of intermediate III disappear substantially；50 DEG C are cooled to, catalyst C-1 is added（14.7g, 0.05mol）, then add
It after heat to back flow reaction 24 hours, removes solvent under reduced pressure, is cooled to room temperature, residue 1.5L dichloromethane dissolves, and is added
1.5L n-hexanes, there is Precipitation, and catalyst is recovered by filtration；Solvent is evaporated off in filtrate decompression, and 1.5L ethyl alcohol, control is added in residue
Temperature is at 5 DEG C hereinafter, 1N hydrochloric acid is added（1.5L）, and maintain after being stirred to react 5 hours at 5 DEG C, with solid sodium bicarbonate tune
PH to 8 is saved, removes solvent, residue dichloromethane under reduced pressure（1.5L）Dissolving, uses water（400ml×2）It is organic relevant after washing
Dry, filtering is dry after removing solvent under reduced pressure, obtains intermediate compound IV shown in formula IV（242.9g, 0.902mol）, molar yield
It is 90.2%, chiral HPLC methods detection producteeValue is 95%.
Embodiment 11：Intermediate V's is synthetically prepared
At room temperature, dichloromethane is sequentially added in reaction bulb（2L）, intermediate compound IV shown in formula IV（269.3g, 1.0mol）、
Di-tert-butyl dicarbonate（261.8g, 1.2mol）, triethylamine（101.2g, 1.0mol）With the 4-dimethylaminopyridine of catalytic amount,
It is stirred to react, TLC detection reactions, until the raw material point of intermediate compound IV disappears, organic phase uses 1N hydrochloric acid successively（400ml）, water
（400ml）Dry after washing, solvent is evaporated off in filtering, filtrate decompression, dry, obtains intermediate V shown in Formula V（352.9g,
0.955mol）, molar yield 95.5%.
Embodiment 12：N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate
（I）Be synthetically prepared
At room temperature, tetrahydrofuran is added in reaction bulb（2L）, stirring is opened, intermediate V shown in Formula V is added（369.5g,
1.0mol）, Lithium Aluminium Hydride is added in batches（57.0g, 1.5mol）, it is warming up to back flow reaction, TLC detection reactions, until intermediate
The raw material point of body V disappears, and after being cooled to room temperature, is slowly added to 600ml water, stirs 30 minutes, after removing organic solvent under reduced pressure, add
Enter ethyl acetate（1.8L）, after stirring 30 minutes, filtering, organic phase water（300ml×2）It is dry after washing, filtering, filtrate
It is dry after removing solvent under reduced pressure, obtain N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] carbamic acid
Tert-butyl ester I（285.5g, 0.872mol）, yield 87.2%.
Claims (7)
1. a planting sand library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxyl first shown in a kind of Formulas I
Base) ethyl] t-butyl carbamate preparation method, preparation methods steps are as follows：
Step 1：4- biphenylcarboxaldehydes and hydantoins hydrolyze after condensation reaction in the presence of base, in obtaining shown in Formula II
Mesosome II；
Step 2：Intermediate III shown in formula III is prepared through esterification in intermediate II shown in Formula II；
Step 3：Intermediate III shown in formula III turns aminating reaction through asymmetry, obtains in the presence of chiral base catalyst
Intermediate compound IV shown in formula IV；
Step 4：Intermediate compound IV shown in formula IV, is protected through Boc, obtains intermediate V shown in Formula V；
Step 5：Sha Kuba songs key intermediate N- shown in Formulas I is prepared through reduction reaction in intermediate V shown in Formula V
[(1R) -2- [1,1 '-biphenyl] -4- bases -1- (hydroxymethyl) ethyl] t-butyl carbamate；
The chemical constitution and synthetic route of intermediate shown in above-described Formulas I, Formula II, formula III, formula IV and Formula V are as follows
It is shown：
。
2. a planting sand according to claim 1 library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1-
(hydroxymethyl) ethyl] t-butyl carbamate preparation method, it is characterised in that the method for step 1 is as follows：
Under 50 ~ 70 DEG C, stirring, a certain amount of hydantoins, ethanol amine or piperidines are added in a certain amount of water, are warming up to
After reflux, the ethanol solution of 4- biphenylcarboxaldehydes is added dropwise, after being added dropwise, continues to maintain the reflux for reacting, TLC detection reactions, until
The raw material point of 4- biphenylcarboxaldehydes disappears；20% sodium hydrate aqueous solution is added, continues back flow reaction 3 ~ 6 hours；Liquid cooling will be reacted
But after partial solvent is evaporated off, solid filtering will be precipitated hereinafter, with concentrated hydrochloric acid adjusting pH to 4 ~ 5 to 5 DEG C, it is dry after filtrate concentration,
Obtain intermediate II shown in Formula II；
Wherein the molar ratio of the 4- biphenylcarboxaldehydes, hydantoins and organic base is 1:1:0.1~0.5.
3. a planting sand according to claim 1 library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1-
(hydroxymethyl) ethyl] t-butyl carbamate preparation method, it is characterised in that the method for step 1 is as follows：
A certain amount of 4- biphenylcarboxaldehydes, hydantoins and ammonium acetate are added in a certain amount of acetic acid, back flow reaction is warming up to,
TLC detection reactions after solvent is evaporated off, adds ethyl alcohol and 20% sodium hydroxide are molten until the raw material point of 4- biphenylcarboxaldehydes disappears
Liquid, continues back flow reaction 3 ~ 6 hours；Reaction solution is cooled to 5 DEG C hereinafter, with concentrated hydrochloric acid tune pH to 4 ~ 5, removes solvent under reduced pressure,
Residue is dissolved with a certain amount of ethyl acetate, and after washing, organic phase drying, filtering is dry after filtrate concentration, obtains Formula II institute
The intermediate II shown；
Wherein the molar ratio of the 4- biphenylcarboxaldehydes, hydantoins and ammonium acetate is 1:1:0.5~2.
4. a planting sand according to claim 1 library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1-
(hydroxymethyl) ethyl] t-butyl carbamate preparation method, it is characterised in that the method for step 2 is as follows：
At room temperature, intermediate II and acid catalyst shown in a certain amount of Formula II are added in a certain amount of absolute ethyl alcohol, are opened
Stirring is opened, back flow reaction is warming up to, TLC detection reactions are cooled to room temperature until the raw material point of intermediate II disappears, and decompression is steamed
After solvent, residue is dissolved with ethyl acetate, and after washing, solvent is evaporated off in organic phase drying, filtering, dry, obtains formula III
Shown in intermediate III；
Wherein one or more mixing in the concentrated sulfuric acid, p-methyl benzenesulfonic acid, trifluoromethane sulfonic acid may be selected in the acid catalyst
Object.
5. a planting sand according to claim 1 library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1-
(hydroxymethyl) ethyl] t-butyl carbamate preparation method, it is characterised in that the method for step 3 is as follows：
Under room temperature and nitrogen protection, in a certain amount of dehydrated organic solvent A, it is added with stirring shown in a certain amount of formula III
Intermediate III and a certain amount of o-chlorine benzylamine, be warming up to back flow reaction, TLC detection reactions, until the raw material of intermediate III
Point disappears；A certain amount of chiral organic alkali catalyst is added, after being reacted 18 ~ 36 hours under 50 DEG C to reflux temperature, decompression is steamed
Except solvent, residue is added a certain amount of ethyl alcohol, control temperature at 5 DEG C hereinafter, a certain amount of 1N hydrochloric acid is added, and 5 DEG C with
Under be stirred to react 1 ~ 5 hour after, adjust pH to 8 with solid sodium bicarbonate, remove solvent under reduced pressure, residue uses dichloromethane molten again
Solution, washing, organic phase drying, filtering is dry after solvent is evaporated off in filtrate decompression, obtains intermediate compound IV shown in formula IV；
Wherein one kind in toluene, benzene, chloroform, dichloromethane, methanol, ethyl alcohol, acetonitrile may be selected in the organic solvent A；
One kind in wherein optional catalyst C-1, C-2, C-3 and C-4 of the chiral organic alkali catalyst, catalyst C-1,
The chemical constitution of C-2, C-3 and C-4 are as follows：
；；
Wherein the molar ratio of intermediate III, o-chlorine benzylamine and chiral organic alkali catalyst shown in the formula III is 1:
1:0.05~0.15。
6. a planting sand according to claim 1 library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1-
(hydroxymethyl) ethyl] t-butyl carbamate preparation method, it is characterised in that the method for step 4 is as follows：
At room temperature, in a certain amount of dichloromethane, intermediate compound IV shown in a certain amount of formula IV, two dimethyl dicarbonate fourths are added
The 4-dimethylaminopyridine of ester, triethylamine and catalytic amount, is stirred to react, TLC detection reactions, until the raw material point of intermediate compound IV disappears
It loses, dry after organic phase washing, filtering is dry after solvent is evaporated off in filtrate decompression, obtains intermediate V shown in Formula V；
The molar ratio of intermediate compound IV, triethylamine, di-tert-butyl dicarbonate described in wherein is 1:1:1.0~1.5.
7. a planting sand according to claim 1 library Ba Qu key intermediates N- [(1R) -2- [1,1 '-biphenyl] -4- bases -1-
(hydroxymethyl) ethyl] t-butyl carbamate preparation method, it is characterised in that the method for step 5 is as follows：
At room temperature, in a certain amount of tetrahydrofuran, stirring is opened, intermediate V shown in Formula V is added, is added in batches certain
The Lithium Aluminium Hydride of amount is warming up to 50 DEG C and is reacted to reflux temperature, and TLC detections are reacted, until the raw material point of intermediate V disappears, room
Temperature is lower to be added a certain amount of water, stirs 30 minutes, after removing organic solvent under reduced pressure, a certain amount of ethyl acetate is added, organic phase
Dry after washing, filtering is dry after solvent is evaporated off in filtrate decompression, obtains intermediate compound I shown in Formulas I.
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