CN105622460B - (R) synthetic method of N tertbutyloxycarbonyls biphenyl Propanolamine - Google Patents

(R) synthetic method of N tertbutyloxycarbonyls biphenyl Propanolamine Download PDF

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CN105622460B
CN105622460B CN201610094826.8A CN201610094826A CN105622460B CN 105622460 B CN105622460 B CN 105622460B CN 201610094826 A CN201610094826 A CN 201610094826A CN 105622460 B CN105622460 B CN 105622460B
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biphenyl
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CN105622460A (en
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赵金浩
黄国传
程敬丽
赵洋
杨勇
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Zhejiang University ZJU
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/02—Preparation of ethers from oxiranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

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Abstract

The invention discloses the synthetic method of one kind (R) N tertbutyloxycarbonyl biphenyl Propanolamines, first by the reaction to bromo biphenyl and (S) benzyloxymethyl oxirane, obtains compound 1；With amine (succimide, adjacent benzene succimide) Mitsunobu reaction generation compounds 2 occur for the next step of compound 1, compound 2 obtains compound 3 by acidolysis reaction, compound 3 reacts to obtain compound 4 by N Boc, and compound 4 obtains required compound 5 (R) N tertbutyloxycarbonyl biphenyl Propanolamines by hydrogenesis again.The synthetic method of the present invention has the advantages that side reaction is few, reaction condition is gentle, high income, workable, product quality are stablized, accessory substance is easily separated, is more suitable for industrialization production.

Description

(R) synthetic method of-N- tertbutyloxycarbonyls biphenyl Propanolamine
Technical field
The present invention relates to the method for the R configuration biphenyl Propanolamines for preparing Boc protections, more particularly to one kind tertiary fourth oxygen of (R)-N- The synthetic method of carbonyl biphenyl Propanolamine.
Background technology
Endogenous atrial natriuretic peptide (ANP), or it is called endogenous atrionatriuretic factor (ANF), have in mammal body There is diuresis, promote natruresis and arterial dilation.Internal ANF peptides are easily by neutral endopeptidase (enkephalin enzyme, NEP) Metabolic inactivation, while NEP can also inactivate enkephalin metabolism.
It is known in the art that the phosphonate derivative of biaryl substituted can be used as neutral endopeptidase (NEP) suppression Preparation, such as the inhibitor as mammal ANF digestive enzymes, so as to be degraded to the relatively low metabolism of activity by developing ANF Product extends and strengthened diuresis, natruresis and vasodilation characteristics of the ANF in mammal body.Therefore, nep inhibitor Suppression available for treatment centering endopeptidase have the situation and illness of response, particularly cardiovascular disorder such as hypertension, Renal insufficiency, including oedema and salt retention, pulmonary edema and congestive heart failure.
(R) structural formula of-N- tertbutyloxycarbonyls biphenyl Propanolamine is：Wherein uncle Boc= Butoxy carbonyl.It is among the key in the synthesis of neutral endopeptidase (NEP) inhibitor to be somebody's turn to do (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines Body (see such as EP00590442 and US4722810).
Several method for preparing (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines has been seen in report.However, these methods All with the expensive raw material (D-Tyrosine of use；J.Med.Chem.1995,38,189 disappear based on) or dependent on outer accordingly The fractionation (EP1980622) of ester is revolved, or use has optically active metal complex to be used as reagent (WO2013026773A1), Financial cost is high；Or synthetic route is cumbersome, (WO2015024991A1) not easy to operate.Patent WO2014032627A1 uses raw material Epoxychloropropane participates in grignard reaction, and exchanging for grignard reagent is easily carried out with grignard reagent and (that is, is also easy to produce height with coupling side reaction The reaction impurities of content, therefore reaction yield is low), or it is anti-to participate in form using S- tert-butoxies oxirane as raw material Should, tert-butoxy is not easy deprotection generation target product in subsequent reactions, therefore, it is necessary to develop a kind of reaction condition gentle, secondary Reaction less, green and suitable industrial method synthesis (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines.
The content of the invention
The technical problem to be solved in the present invention is to provide (R)-N- tertiary butyloxycarbonyls that a kind of reaction condition is gentle, green The synthetic method of base biphenyl Propanolamine.
In order to solve the above-mentioned technical problem, the present invention provides the synthesis side of one kind (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines Method, follow the steps below successively：
1), put into using magnesium and as the anhydrous tetrahydro furan of solvent in reaction bulb, it is warming up to 35 under nitrogen protection~ 55 DEG C (preferably 40~45 DEG C), add iodine and addition prepare grignard reagent to bromo biphenyl/tetrahydrofuran solution, to bromo biphenyl Mol ratio with magnesium is 1:1~1.5 (preferably 1:1~1.2), iodine is with being 0.1%~0.5% to the weight ratio of bromo biphenyl, instead It is 2~6h (preferably 2~4h) between seasonable；
Then reaction temperature is reduced to -15~0 DEG C (preferably -15~-5 DEG C), adds cuprous iodide, then (S)-benzyl is added dropwise Oxygen methyl oxirane/tetrahydrofuran solution, it is 1 to the mol ratio of bromo biphenyl and cuprous iodide:0.1~0.5, to bromo biphenyl with (S) mol ratio of-benzyloxymethyl oxirane is 1:1~1.5 (preferably 1:1.1~1.3), the reaction time is 2~6h (preferable For 2~4h), obtain compound 1；The structural formula of the compound 1 is：
Remarks explanation：Grignard reagent is the high activity intermediate of prepare compound 1；To bromo biphenyl, i.e. 4- bromo biphenyls；Iodine It is catalyst, and judges the color indicator that reaction starts；To bromo biphenyl/tetrahydrofuran solution, i.e. bromo biphenyl will be dissolved in Solution obtained by tetrahydrofuran；Remaining is by that analogy；
2), by compound 1, triphenylphosphine, R1- H and low polar solvent mixing, compound 1 and the mol ratio of triphenylphosphine For 1:1~2 (preferably 1:1~1.2), compound 1 and R1- H mol ratio is 1:1~2 (preferably 1:1~1.2), in nitrogen The lower controlling reaction temperature of protection is -1~15 DEG C, adds azoformic acid diester and carries out insulation reaction, compound 1 and azo two The mol ratio of formic acid diester is 1:1~2 (preferably 1:1~1.2), the reaction time is 2~6h (preferably 2~4h), is changed Compound 2；R1- H is succimide, adjacent benzene succimide (phthalimide)；
The structural formula of the compound 2 is：
3), using water as solvent, compound 2 is to be reacted under 0.5~1 acid condition in pH, reaction temperature 60 ~100 DEG C, the reaction time is 6~15h (preferably 6~10h), obtains compound 3；The structural formula of the compound 3 is：
4), using alcohol-water mixture as solvent, using sodium hydroxide as acid binding agent, compound 3 and di-tert-butyl dicarbonate (Boc2O) reacted, compound 3 and di-tert-butyl dicarbonate (Boc2O mol ratio) is 1:1~2 (preferably 1:1~ 1.2), compound 3 and the mol ratio of sodium hydroxide are 1：1~2.5 (preferably 1:1.1~1.3)；Reaction temperature is 20~60 DEG C, the reaction time is 2~6h (preferably 2~4h), obtains compound 4；The structural formula of the compound 4 is：
5), using alcohol as solvent, H is utilized2Pressure is adjusted to 0.5~3Mpa (preferably 1~1.5Mpa), compound 4 and Pd/ Reacted after C mixing；Pd mass content is 10% in the Pd/C；The mol ratio of Pd in compound 4 and Pd/C is 1: 0.001~0.004 (preferably 1:0.003~0.004)；Reaction temperature is 25~60 DEG C, and the reaction time is that 2~16h (is preferably 2~4h), obtain compound 5；The compound 5 is (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines, and its structural formula is：
Improvement as the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the present invention：In the step 2)：
The azoformic acid diester is diethyl azodiformate (diethylazodicarboxylate), azoformic acid two is different Propyl ester, di tert butyl carbonate；
Low polar solvent is tetrahydrofuran, ether, dichloromethane, toluene, ethyl acetate, acetonitrile.
Further improvement as the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the present invention：
In the alcohol-water mixture of the step 4), the volume content of water is 20~80%；The alcohol is methanol or ethanol；
The alcohol of the step 5) is methanol or ethanol.
Further improvement as the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the present invention：
Acid used is organic acid or inorganic acid in the step 3), and organic acid is formic acid and acetic acid；Inorganic acid be hydrochloric acid, Sulfuric acid.
Further improvement as the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the present invention：
Magnesium in step 1) is magnesium powder, magnesium chips or magnesium rod.
Further improvement as the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the present invention：
Magnesium in step 1) is preferably magnesium powder (sieve that can cross 200 mesh)；
Preferable reaction temperature in step 2) is -1~5 DEG C；
Preferable reaction temperature in step 3) is 80~100 DEG C (being more preferably 80~90 DEG C)；
Preferable reaction temperature in step 4) is 35~60 DEG C；
Preferable reaction temperature in step 5) is 35~40 DEG C.
In the present invention, general control is added dropwise to complete in 1~2 hour.
The synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the present invention, flow chart are as shown in Figure 1.The present invention is logical The reaction to bromo biphenyl and (S)-benzyloxymethyl oxirane is crossed, obtains compound 1；The next step of compound 1 and amine (succinyl Imines, adjacent benzene succimide) Mitsunobu reaction generation compounds 2 occur, compound 2 obtains chemical combination by acidolysis reaction Thing 3, compound 3 react to obtain compound 4 by N-Boc, and compound 4 obtains required compound by hydrogenesis again 5--- (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines.
In the present invention, following abbreviation has been used：Bn=benzyls, DEAD=diethyl azodiformates, the tertiary fourth oxygen of Boc= Carbonyl.R1- H title and structural formula is as shown in the table：
In the present invention,
To the reaction solution generated after the completion of the grignard reaction of step 1), the conventional treatment side for such as extracting, concentrating can be used Method handles reaction solution, or preferably mode is to adjust reaction solution to acidity, wash again several times, then by organic phase solution Be concentrated under reduced pressure into it is dry, so as to obtain the crude product of compound 1.Above-mentioned crude product can be directly used for following step 2) reaction.Can also This crude product is refined with toluene, obtains the compound 1 of high-purity；The compound 1 of high-purity is used for following step 2 again) it is anti- Should.
In step 1), preferably reacted in anhydrous tetrahydro furan.
To the reaction solution generated after the completion of the Mitsunobu reactions of step 2), it can use and such as extract, at the routine of concentration Reason method handles reaction solution, or preferably mode is to be directly thickened to do；So as to obtain the crude product of compound 2.Above-mentioned crude product Can be directly used for following step 3) reaction.
In step 2), preferably reacted in toluene.
To the reaction solution generated after the completion of the heating response of step 3), it can use and such as extract, wash, at the routine of concentration Reason method handles reaction solution, or preferably mode wash several times with toluene, then by aqueous phase solution regulation PH to alkalescence, So as to separate out to obtain the crude product of compound 3.Above-mentioned crude product can be directly used for following step 4) reaction.
In step 3), preferably reacted in pure water.
To the reaction solution generated after the completion of the heating response of step 4), it can use and such as extract, wash, at the routine of concentration Reason method handles reaction solution, or preferably mode is directly by the alcoholic solvent evaporated under reduced pressure in reaction solution, so as to be tied in water Crystalline substance goes out the crude product of compound 4.Above-mentioned crude product can be directly used for following step 5) reaction.
In step 4), preferably reacted in 50% ethanol water.
To the reaction solution generated after the completion of the heating response of step 5), it can use and such as extract, wash, at the routine of concentration Reason method handles reaction solution, or preferably mode be directly by reaction solution evaporated under reduced pressure, so as to obtain the crude product of compound 5, Above-mentioned crude product is again with crystal's system, so as to obtain the compound 5 of high-purity.
In step 5), preferably reacted in ethanol.
The synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the present invention, with to bromo biphenyl and (S)-benzyloxymethyl ring Oxidative ethane is raw material, and (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines can be made by the reaction of simple five step.The system of the present invention Standby method need not be expensive raw material based on or the fractionation dependent on corresponding racemate, it is not required that using there is optics work The metal complex of property is used as reagent, it is not necessary to use special reagent；And raw material can be directly commercially available, and be greatly reduced Production cost, and the step total recovery of preparation method five of the present invention is up to 62.4%.
In summary, synthetic method of the invention have side reaction is few, reaction condition is gentle, high income, workable, production The advantages that quality is stable, accessory substance is easily separated, is more suitable for industrialization production.The present invention relative to WO2014032627A1 and Speech, improves reaction yield.
Brief description of the drawings
The embodiment of the present invention is described in further detail below in conjunction with the accompanying drawings.
Fig. 1 is the flow chart of the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines of the invention.
Embodiment
Involved dropwise addition was completed in 1~2 hour in the step of following cases.
For the ease of being further appreciated that to the present invention, embodiment is provided below more detailed description has been done to it.These Embodiment is only not used for limiting the scope of the present invention or implementation principle for narration.
The preparation method of embodiment 1, one kind (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines, is followed the steps below successively：
1), the preparation of compound 1：
4.94g (0.21mol) magnesium powders and the anhydrous THF of 88g, stirring are added in 500ml four-hole boiling flasks；Obtain magnesium/tetrahydrofuran Solution.
One pot of parallel reaction separately is opened, 46.6g 4- bromo biphenyls (0.20mol) is added in 250ml flasks and 88g is anhydrous THF, stirring, obtains 4- bromo biphenyls/tetrahydrofuran solution；It is standby.
Reaction system (magnesium/tetrahydrofuran solution) is heated to 40 ± 1 DEG C, under heat-retaining condition under nitrogen protection, anti-to this Answer system to add iodine (0.047g) while stirring and account for the 4- bromo biphenyls tetrahydrofuran solution (about 25ml) of total amount 1/4, then, remain The 4- bromo biphenyl tetrahydrofuran solutions of remaining (that is, account for total amount 3/4) are added in a manner of being added dropwise, and insulation 2h enters after dripping Row reaction.- 5 ± 1 DEG C is cooled to after having reacted, adds 3.81g (0.02mol) cuprous iodide, then keeping temperature is added dropwise (S) [39.4g (0.24mol) (s)-benzyloxymethyl oxirane is dissolved in 30g tetra- to-benzyloxymethyl oxirane/tetrahydrofuran solution Hydrogen furans], insulation 2h after dripping.
120.4g 4M HCl solutions, stirring are added in the reaction solution of gained.Then, solution is layered, collected organic layer (position In upper strata), water layer is washed with 80ml THF, is washed after the cleaning solution of gained and organic layer are merged with saturated aqueous common salt 100ml Wash, concentration (in 45 ± 5 DEG C of concentrations until there is no the generation of new solid), solid filtering, filter cake pure water, vacuum 55- 60 DEG C of dryings, finally obtain yellow powder solid (compound 1) 56.0g, yield 88.2%.
1H-NMR(500MHz,CDCl3,δppm):7.59-7.57 (m, 4H, Ar-H), 7.41 (d, J=9.12Hz, 2H, Ar- ), H 7.39 (d, J=9.18Hz, 2H, Ar-H), 7.38-7.34 (m, 3H, Ar-H), 7.32-7.29 (m, 3H, Ar-H), 4.52 (s,2H,CH2), 4.12-4.11 (m, 1H, CH), 3.58 (d, J=9.33Hz, 2H, CH2), 2.96 (d, J=5.5Hz, 2H, CH2), 2.31 (dd, J=0.6Hz, 1H, OH).
2), compound 2-1 preparation：
63.6g (0.20mol) compound 1 and 600g toluene are added in 1000ml four-hole boiling flasks, stirring is until all dissolvings. Solution is cooled to 0 ± 1 DEG C under nitrogen protection, adds 57.64g (0.22mol) triphenylphosphines and 20.79g (0.22mol) fourth two Acid imide, then add diethylazodicarboxylate's solution [40.02g (0.20mol) azodicarboxy while stirring at 0 ± 1 DEG C Diethyl phthalate is dissolved in 40g toluene], insulation reaction 2h.
The reaction solution of gained, which is evaporated under reduced pressure, removes toluene, and substrate is directly used in next step.Contain compound 2- in the substrate 1。
1H-NMR(500MHz,CDCl3,δppm):7.71-7.65 (m, 4H, Ar-H), 7.64 (d, J=9.33Hz, 2H, Ar- ), H 7.61 (d, J=8.33Hz, 2H, Ar-H), 7.56-7.45 (m, 3H, Ar-H), 7.38-7.31 (m, 3H, Ar-H), 4.72 (s,2H,CH2), 4.42-4.32 (m, 1H, CH), 3.67 (d, J=10.32Hz, 2H, CH2), 3.05 (d, J=5.8Hz, 2H, CH2),2.73-2.77(m,4H,CH2)。
3), the preparation of compound 3：
300g water add above-mentioned steps 2) obtain substrate in, be heated to 80 ± 1 DEG C, be slowly added to HCl until regulation body The pH value of system is 1.Then insulated and stirred 6h.
After the reaction product of gained is cooled to room temperature, 433g toluene is added, 80 ± 1 DEG C of stirring 30min is heated to, cools down, Solution is layered, and collects water layer (being located at lower floor), is adjusted PH=9-10 using the sodium hydrate aqueous solution that concentration is 30%, is separated out production Thing, cold filtration, finally obtain white solid (compound 3) 51.3g, yield 81.2%.
1H-NMR(500MHz,CDCl3,δppm):7.77-7.71 (m, 4H, Ar-H), 7.69 (d, J=9.33Hz, 2H, Ar- ), H 7.64 (d, J=10.12Hz, 2H, Ar-H), 7.59-7.56 (m, 3H, Ar-H), 7.49-7.45 (m, 3H, Ar-H), 5.11 (d, J=7.2Hz, 2H, NH2),4.38(s,2H,CH2), 4.32-4.22 (m, 1H, CH), 3.46 (d, J=8.12Hz, 2H, CH2), 2.85 (d, J=6.4Hz, 2H, CH2)。
4), the preparation of compound 4：
Add 63.4g (0.20mol) compound 3 in 1000ml four-hole boiling flasks, 200g water and 160g ethanol, stirring until Dissolving, then, 9.6g (0.24mol) sodium hydroxide is added, is heated to 55 ± 1 DEG C, then add 48.4g (0.22mol) two carbon Sour di tert butyl carbonate, keeping temperature stirring 2h.
By the reaction solution vacuum fractionation of gained, until removing all ethanol, then mother liquor cools down, precipitate filtering, filter cake It is washed with water, dries (55-60 DEG C of drying temperature) in air dry oven, obtain white solid (compound 4) 79.2g, receives Rate 95.2%.
1H-NMR(500MHz,CDCl3,δppm):7.82-7.76 (m, 4H, Ar-H), 7.72 (d, J=9.33Hz, 2H, Ar- ), H 7.69 (d, J=10.12Hz, 2H, Ar-H), 7.64-7.58 (m, 3H, Ar-H), 7.52-7.44 (m, 3H, Ar-H), 5.84 (d, J=8.2Hz, 1H, NH), 4.41 (s, 2H, CH2), 4.35-4.32 (m, 1H, CH), 3.72 (d, J=8.12Hz, 2H, CH2), 2.75 (d, J=8.33Hz, 2H, CH2).1.38(s,9H,CH3)。
5), the preparation of compound 5：
83.4g (0.20mol) compound 4 is added in 1000ml autoclaves, 300g ethanol, stirring is up to dissolving, then, 0.8g10%Pd/C (that is, Pd is 0.0007mol), Hydrogen Vapor Pressure 1MPa are added, is heated to 45 ± 1 DEG C of keeping temperature stirrings 4h。
By the reacting liquid filtering of gained, filtrate decompression fractionation until remove all ethanol, obtain white solid (compound 5, That is, (R)-N- tertbutyloxycarbonyl biphenyl Propanolamine) 60.8g, yield 93.0%.
1H-NMR(500MHz,CDCl3,δppm):7.54-7.49 (m, 4H, Ar-H), 7.48 (d, J=9.56Hz, 2H, Ar- ), H 7.30-7.24 (m, 3H, Ar-H), 6.04 (d, J=9.12Hz, 1H, NH), 4.72 (d, J=7.2Hz, 1H, OH), 4.24- 4.20 (m, 1H, CH), 3.74 (d, J=8.56Hz, 2H, CH2), 2.57 (d, J=4.8Hz, 2H, CH2).1.28(s,9H,CH3)。
The step total recovery of the above five is 63.4%.
The preparation method of embodiment 2, one kind (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines, is followed the steps below successively：
1), the preparation of compound 1：
0.99g (0.041mol) magnesium powders and the anhydrous THF of 18g, stirring are added in 100ml four-hole boiling flasks；Obtain magnesium/tetrahydrofuran Solution.
One pot of parallel reaction separately is opened, 9.3g 4- bromo biphenyls (0.040mol) and the anhydrous THF of 18g are added in 50ml flasks, Stirring, obtains 4- bromo biphenyls/tetrahydrofuran solution, standby.
Reaction system (magnesium/tetrahydrofuran solution) is heated to 45 ± 1 DEG C under nitrogen protection.Under heat-retaining condition, to magnesium/tetra- In hydrogen tetrahydrofuran solution, iodine (0.0465g) and account for the 4- bromo biphenyls tetrahydrofuran solution (about 5ml) of total amount 1/4 and add while stirring, Then, remaining 4- bromo biphenyls tetrahydrofuran solution (that is, account for total amount 3/4) is added in a manner of dropwise addition, is protected after dripping Warm 4h.- 14 ± 1 DEG C is cooled to after having reacted, adds 0.76g (0.0040mol) cuprous iodide, then keeping temperature is added dropwise molten Liquid [7.9g (0.048mol) (s)-benzyloxymethyl oxirane is dissolved in 6g tetrahydrofurans], insulation 4h after dripping.
24g 4M HCl solutions, stirring are added in the reaction solution of gained.Then, solution is layered, collected organic layer, and water layer is used THF is washed, and is used saturated common salt water washing after the cleaning solution of gained and organic layer are merged, is concentrated, solid filtering, filter cake pure water Washing, 55-60 DEG C of drying of vacuum, finally obtains yellow powder solid 10.0g, yield 79%.MS-ESI:319(M+1, 100%).
2), compound 2-2 preparation：
10.6g (0.033mol) compound 1 and 100g toluene are added in 250ml four-hole boiling flasks, stirring is until all dissolvings. Solution is cooled to 5 ± 1 DEG C under nitrogen protection, adds 9.6g (0.036mol) triphenylphosphines and the adjacent benzene fourths of 5.2g (0.036mol) Imidodicarbonic diamide, then add diethylazodicarboxylate's solution [6.7g (0.033mol) azo two while stirring at 5 ± 1 DEG C Carboxylic acid diethylester is dissolved in 6g toluene], insulation reaction 4h.
The reaction solution of gained, which is evaporated under reduced pressure, removes toluene, and substrate is directly used in next step.Contain compound 2- in the substrate 2。
1H-NMR(500MHz,CDCl3,δppm):7.82-7.80(m,2H,Ar-H),7.78-7.74(m,2H,Ar-H), 7.71-7.68 (m, 4H, Ar-H), 7.59 (d, J=9.33Hz, 2H, Ar-H), 7.52 (d, J=10.12Hz, 2H, Ar-H), 7.49-7.45(m,3H,Ar-H),7.42-7.38(m,3H,Ar-H),4.15(s,2H,CH2),3.85-3.82(m,1H,CH), 3.64 (d, J=8.42Hz, 2H, CH2), 2.47 (d, J=4.12Hz, 2H, CH2)。
3), the preparation of compound 3：
50g water adds above-mentioned steps 2) in the substrate that obtains, 90 ± 1 DEG C are heated to, is slowly added to HCl until regulation system PH value be 1.Then insulated and stirred 10h.
After the reaction product of gained is cooled to room temperature, 72.1g toluene is added, 90 ± 1 DEG C of stirring 30min is heated to, cools down, Solution is layered, and collects water layer, adjusts PH=9-10, is separated out product, cold filtration, is finally obtained white solid 7.7g, yield 73.9%.MS-ESI:318 (M+1,100%).
4), the preparation of compound 4：
10.6g (0.033mol) compound 3,30g water and 25g ethanol are added in 250ml four-hole boiling flasks, stirring is until molten Solution, then, 1.6g (0.040mol) sodium hydroxide is added, is heated to 35 ± 1 DEG C, then add 8.1g (0.037mol) two carbonic acid Di tert butyl carbonate, keeping temperature stirring 4h.
By the reaction solution vacuum fractionation of gained, until removing all ethanol, then mother liquor cools down, precipitate filtering, filter cake It is washed with water, is dried in air dry oven, obtains white solid 12.5g, yield 90.2%.MS-ESI:418(M+1, 100%).
5), the preparation of compound 5：
13.9g (0.033mol) compound 4 is added in 250ml autoclaves, 50g ethanol, stirring is up to dissolving, then, 0.12g10%Pd/C (that is, Pd is 0.00011mol) is added, Hydrogen Vapor Pressure 1.5MPa, 35 ± 1 DEG C of keeping temperatures is heated to and stirs Mix 2h.
By the reacting liquid filtering of gained, filtrate decompression fractionation obtains white solid 9.65g until all ethanol of removing, received Rate 90.0%.MS-ESI:328 (M+1,100%).
The step total recovery of the above five is 47.3%.
Embodiment 3, make the diethylazodicarboxylate in the step 2) of embodiment 1 into diisopropyl azodiformate, rub Your amount is constant；Remaining is equal to embodiment 1.Five step total recoverys are 57.5%.
Embodiment 4, make the diethylazodicarboxylate in the step 2) of embodiment 1 into di tert butyl carbonate, mole is constant；Its It is remaining to be equal to embodiment 1.Five step total recoverys are 65.2%.
Finally, it is also necessary to it is noted that listed above is only several specific embodiments of the invention.Obviously, this hair It is bright to be not limited to above example, there can also be many deformations.One of ordinary skill in the art can be from present disclosure All deformations for directly exporting or associating, are considered as protection scope of the present invention.

Claims (5)

  1. The synthetic method of (1. R)-N- tertbutyloxycarbonyl biphenyl Propanolamines, it is characterized in that following the steps below successively：
    1), put into using magnesium and as the anhydrous tetrahydro furan of solvent in reaction bulb, be warming up to 35~55 DEG C under nitrogen protection, Add iodine and add and prepared by RMgBr to bromo biphenyl/tetrahydrofuran solution, be 1 to the mol ratio of bromo biphenyl and magnesium:1~ 1.5, iodine is 0.1%~0.5% with the weight ratio to bromo biphenyl, and the reaction time is 2~6h；
    Then reaction temperature is reduced to -15~0 DEG C, adds cuprous iodide, then (S)-benzyloxymethyl oxirane/tetrahydrochysene furan is added dropwise Mutter solution, be 1 to the mol ratio of bromo biphenyl and cuprous iodide:0.1~0.5, to bromo biphenyl and (S)-benzyloxymethyl oxirane Mol ratio be 1:1~1.5, the reaction time is 2~6h, obtains compound 1；The structural formula of the compound 1 is：
    2), by compound 1, triphenylphosphine, R1The mol ratio of-H and low polar solvent mixing, compound 1 and triphenylphosphine is 1:1 ~2, compound 1 and R1- H mol ratio is 1:1~2, controlling reaction temperature is -1~15 DEG C under nitrogen protection, adds idol The mol ratio of nitrogen dicarboxylate progress insulation reaction, compound 1 and azoformic acid diester is 1:1~2, the reaction time 2 ~6h, obtain compound 2；R1- H is succimide, adjacent benzene succimide；
    The azoformic acid diester is diethyl azodiformate, diisopropyl azodiformate, two tertiary fourth of azoformic acid Ester；
    The low polar solvent is tetrahydrofuran, ether, dichloromethane, toluene, ethyl acetate, acetonitrile；
    The structural formula of the compound 2 is：
    3), using water as solvent, compound 2 is to be reacted under 0.5~1 acid condition in pH, and reaction temperature is 60~100 DEG C, the reaction time is 6~15h, obtains compound 3；The structural formula of the compound 3 is：
    4), using alcohol-water mixture as solvent, using sodium hydroxide as acid binding agent, compound 3 carries out anti-with di-tert-butyl dicarbonate Should, the mol ratio of compound 3 and di-tert-butyl dicarbonate is 1:1~2, the mol ratio of compound 3 and sodium hydroxide is 1：1~ 2.5；Reaction temperature is 20~60 DEG C, and the reaction time is 2~6h, obtains compound 4；The structural formula of the compound 4 is：
    5), using alcohol as solvent, H is utilized2Regulation pressure to 0.5~3Mpa, compound 4 is reacted after being mixed with Pd/C；It is described Pd mass content is 10% in Pd/C；The mol ratio of Pd in compound 4 and Pd/C is 1:0.001~0.004；Reaction temperature For 25~60 DEG C, the reaction time is 2~16h, obtains compound 5；The compound 5 is (R)-N- tertbutyloxycarbonyls the third ammonia of biphenyl Alcohol, its structural formula are：
  2. 2. the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines according to claim 1, it is characterized in that：
    In the alcohol-water mixture of the step 4), the volume content of water is 20~80%；The alcohol is methanol or ethanol；
    The alcohol of the step 5) is methanol or ethanol.
  3. 3. the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines according to claim 1, it is characterized in that：
    Acid used is organic acid or inorganic acid in the step 3), and organic acid is formic acid and acetic acid；Inorganic acid is hydrochloric acid, sulphur Acid.
  4. 4. the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines according to claim 1, it is characterized in that：
    Magnesium in step 1) is magnesium powder, magnesium chips or magnesium rod.
  5. 5. the synthetic method of (R)-N- tertbutyloxycarbonyl biphenyl Propanolamines according to claim 1, it is characterized in that：
    Magnesium in step 1) is magnesium powder；
    Reaction temperature in step 2) is -1~5 DEG C；
    Reaction temperature in step 3) is 80~100 DEG C；
    Reaction temperature in step 4) is 35~60 DEG C；
    Reaction temperature in step 5) is 35~40 DEG C.
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