CN106588698A - Preparation method of N-Boc biphenyl alaninal - Google Patents
Preparation method of N-Boc biphenyl alaninal Download PDFInfo
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- CN106588698A CN106588698A CN201611015731.9A CN201611015731A CN106588698A CN 106588698 A CN106588698 A CN 106588698A CN 201611015731 A CN201611015731 A CN 201611015731A CN 106588698 A CN106588698 A CN 106588698A
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- oxidation reaction
- boc
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- biphenyl
- iodosobenzoic acids
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- 239000004305 biphenyl Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims description 65
- 235000010290 biphenyl Nutrition 0.000 title claims description 47
- QPMCUNAXNMSGTK-UHFFFAOYSA-N 2-aminopropanal Chemical compound CC(N)C=O QPMCUNAXNMSGTK-UHFFFAOYSA-N 0.000 title abstract 3
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 39
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 38
- IFPHDUVGLXEIOQ-UHFFFAOYSA-N ortho-iodosylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1I=O IFPHDUVGLXEIOQ-UHFFFAOYSA-N 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 19
- -1 ammonium aldehyde Chemical class 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 230000001590 oxidative effect Effects 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 150000002825 nitriles Chemical group 0.000 claims description 5
- 238000012805 post-processing Methods 0.000 claims description 5
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- OWQCENTZHZJGTR-UHFFFAOYSA-N tert-butyl 2-phenylbenzoate Chemical group CC(C)(C)OC(=O)C1=CC=CC=C1C1=CC=CC=C1 OWQCENTZHZJGTR-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 8
- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Natural products CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940100321 entresto Drugs 0.000 description 2
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 description 2
- 229960003953 sacubitril Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 241000206601 Carnobacterium mobile Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 210000000607 neurosecretory system Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of N-Boc-biphenyl alaninal, and the preparation method comprises the following steps: the N-Boc-biphenyl alaninal can be obtained by oxidation reaction of N-Boc-biphenyl alaninol and 2-iodoxybenzoic acid in an organic solvent. The method has the advantages of simple operation, high yield, high purity, low cost and little pollution, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of the ammonium aldehyde of N-Boc biphenyl third, belongs to field of medicine and chemical technology.
Background technology
The new drug Entresto of the treatment angiocardiopathy that Novartis Co., Ltd releases recently, for treating II-IV grade of heart of NYHA
Decline patient, in many ways cardioactive neuroendocrine system.Entresto is the anti-hypertension for losing patent protection
Medicine Valsartan and a kind of combination drug of novel antihypertensive medicament Sacubitril, for the treatment of heart failure.
For the synthesis of newtype drug Sacubitril enkephalinase inhibitors, though document has the report of several different routes
Road, but the conversion that N-Boc biphenyl Propanolamines are converted into the ammonium aldehyde of N-Boc biphenyl third is directed to mostly.Relevant this oxidizing process,
Nine divisions of China in remote antiquity medicine company and Novartis Co., Ltd are only seen at present reports the technique using TEMPO catalysis oxidations in WO2014032627.The work
The advantage of skill is that raw material is relatively inexpensive, but cumbersome, and solvent load is big, and system is huge, and the yield of products therefrom is typically 70
～75%.
Therefore, this area need badly a kind of simple to operate, high income, purity height, low cost, pollution less, be adapted to industrial metaplasia
The preparation method of the ammonium aldehyde of N-Boc- biphenyl third of product.
The content of the invention
Problem to be solved by this invention be the existing ammonium aldehyde of N-Boc- biphenyl third preparation method is cumbersome, yield is low
Etc. defect, thus, the invention provides a kind of preparation method of the ammonium aldehyde of N-Boc- biphenyl third.The method is simple to operate, high income,
Purity height, low cost, pollution less, be adapted to industrialized production.
The invention provides a kind of preparation method of the ammonium aldehyde of N-Boc- biphenyl third, it comprises the steps：In organic solvent
In, N-Boc- biphenyl Propanolamine and 2- iodosobenzoic acids (IBX) are carried out into oxidation reaction, obtain the ammonium aldehyde of N-Boc- biphenyl third i.e.
Can；
Wherein, " * " in described N-Boc- biphenyl Propanolamine and the described ammonium aldehyde of N-Boc- biphenyl third represents mark
Carbon atom is asymmetric carbon atom, and its configuration it is identical (therefore, described N-Boc- biphenyl Propanolamine and described N-Boc- biphenyl
Third ammonium aldehyde is simultaneously R configurations, S configurations or, the mixture of R configurations and S configurations；Namely there is no configuration reversal in the reaction).
In described oxidation reaction, described organic solvent can be the conventional organic solvent of such reaction of this area, this
Invent one or more in particularly preferred nitrile solvents, aromatic hydrocarbon solvent and ether solvent, further preferred ether solvent.
Described ether solvent can be the conventional ether solvent of such reaction of this area, 1,2- dimethoxy-ethanes specifically preferred according to the invention
(DME).Described aromatic hydrocarbon solvent can be the conventional aromatic hydrocarbon solvent of such reaction of this area, first specifically preferred according to the invention
Benzene.Described nitrile solvents can be the conventional nitrile solvents of such reaction of this area, acetonitrile specifically preferred according to the invention.
In described oxidation reaction, the volume mass ratio of described organic solvent and described N-Boc- biphenyl Propanolamines
Can be the conventional volume mass ratio of such reaction of this area, preferably 3～12mL/g is more preferably 4～8mL/g, most preferably
For 5～6mL/g.
In described oxidation reaction, described 2- iodosobenzoic acids and described N-Boc- biphenyl Propanolamines mole
Than being the conventional mol ratio of such reaction of this area, preferably 1.0～2.0, more preferably for 1.1～1.6 (such as 1.3～
1.4)。
In described oxidation reaction, the temperature of described oxidation reaction can be the conventional temperature of such reaction of this area,
Preferably 30～120 DEG C (and such as 110 DEG C), are more preferably 50～90 DEG C, are most preferably 75～85 DEG C.
In described oxidation reaction, described oxidation reaction such reaction conventional detection mode can be carried out using this area
Monitoring, such as thin-layer chromatography (TLC).When reaction end monitoring is carried out with TLC, typically no longer reacted with N-Boc- biphenyl Propanolamines
As the terminal of reaction.The time of described oxidation reaction can be (such as 0.5～2 hour, and such as 1 is little 0.5～3 hour
When).
Described oxidation reaction can also include the conventional post processing of such reaction of this area.It is preferred that described oxidation is anti-
Following post-processing steps should also be included：Cooling (being for example down to room temperature), filters, with above-mentioned organic solvent washing filter cake (i.e. 2-
Iodosobenzoic acid crude product), filtrate concentration (partially completely removes reaction dissolvent, above-mentioned organic solvent), recrystallization
(recrystallization solvent can be ethyl acetate/normal heptane), obtains the described ammonium aldehyde of N-Boc- biphenyl third.
It is preferred that the post-processing step of described oxidation reaction also comprises the steps, in processing in the above-mentioned latter
The filter cake (i.e. 2- iodosobenzoic acids crude product) that obtains is reoxidized for 2- iodosobenzoic acids, so as to realize recycling,
And work well：In water, described filter cake (i.e. 2- iodosobenzoic acids crude product) and oxidant are carried out into oxidation reaction, obtained
To 2- iodosobenzoic acids；
In the preparation method of described 2- iodosobenzoic acids, described oxidant can be such reaction routine of this area
Oxidant (such as potassium permanganate or potassium hydrogen persulfate), preferably potassium hydrogen persulfate.
In the preparation method of described 2- iodosobenzoic acids, described oxidant and described filter cake (i.e. 2- idous
Acyl group benzoic acid crude product) mol ratio can be the conventional mol ratio of such reaction of this area, preferably 2.0～3.6, more preferably
For 2.7～3.0.When the mole of described filter cake is calculated, it is assumed that described filter cake is 2- iodosobenzoic acid sterlings.
In the preparation method of described 2- iodosobenzoic acids, the temperature of described oxidation reaction can for this area such
The conventional temperature of reaction, preferably 30～100 DEG C, be more preferably 50～90 DEG C, is most preferably 65～75 DEG C.
In the preparation method of described 2- iodosobenzoic acids, described oxidation reaction can be using such reaction of this area
Conventional detection mode is monitored, such as thin-layer chromatography (TLC).When reaction end monitoring is carried out with TLC, typically with 2- iodosos
Yl benzoic acid residual is less than 2% as the terminal of reaction.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：The method is simple to operate, high income, purity height, low cost, pollution less,
Suitable industrialized production
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.
The measuring method of embodiment moderate purity is as follows：HPLC, chromatographic column：Gemini C18,250 × 4.6mmID, 5 μm, stream
Speed：1.0mL/min, column temperature：30℃.Mobile phase A (20mM KH2PO4The aqueous solution, adds 6mol/L KOH to adjust pH=10), stream
Dynamic phase B (MeOH).Gradient:0min (70%A)；20min (30%A)；40min (30%A).Acquisition time：40 minutes.
Retention time：
(R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- aminopropanols：30.3min
(R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- amido propionic aldehyde：32.0min
2- iodosobenzoic acids：3.4min
2- iodosobenzoic acids：4.2min
Embodiment 1 (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- amido propionic aldehyde
In the round-bottomed flask of 1L, 105g (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- aminopropanols are dissolved in
In 600mL DME, under stirring, 117g IBX are added.After adding, reaction system is heated to into 75-85 DEG C, is reacted 1 hour
Left and right monitors to raw material and disappears, and reaction system is cooled down to into room temperature.Filter, filter cake 50mL DME drip washing, after filter cake is collected
As 2- iodosobenzoic acids, for follow-up recovery, after filtrate reduced in volume, with ethyl acetate/normal heptane crystallization, drying
After obtain white solid 101g, as target product.Yield 96.6%, purity>99%.
1H-NMR(400MHz,CDCl3):δ=9.69 (s, 1H), 7.59 (t, 4H), 7.46 (t, 2H), 7.38 (t, 1H),
7.28(d,2H),5.13(d,1H),4.48(q,1H),3.18(d,2H),1.47(s,9H)。
Embodiment 2 prepares IBX with the 2- iodosobenzoic acids for reclaiming
In the round-bottomed flask of 1L, the 2- iodosobenzoic acids reclaimed in 40g above-described embodiments 1 are added, add configuration
(145g potassium hydrogen persulfates are dissolved in 500mL water good hydrogen persulfate aqueous solutions of potassium, and the active constituent content of potassium hydrogen persulfate is
42.8%).After adding, reaction system is heated to into 65-75 DEG C, is reacted 3 hours or so, monitored to 2- idous acyl group benzene first
Acid residual is less than 2%.Reaction system is cooled down to into 0-5 DEG C, is stirred 2 hours.Filter, filter cake is washed with water repeatedly, after drying
Obtain white solid 38.6g, as IBX.The rate of recovery 85.4%, purity>98%.
(IBX is with the 2- iodosos for reclaiming to embodiment 3 (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- amido propionic aldehyde
Yl benzoic acid prepares gained)
In the round-bottomed flask of 250mL, 26g (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- aminopropanols are dissolved in
In 160mL DME, under stirring, the IBX that preparation is reclaimed in 29g embodiments 2 is added.After adding, reaction system is heated to
75-85 DEG C, reaction is monitored to raw material and disappeared for 1 hour or so, and reaction system is cooled down to into room temperature.Filter, filter cake 15mL
DME drip washing, as 2- iodosobenzoic acids after filter cake collection, can be repeated for follow-up recovery.After filtrate reduced in volume, use
Ethyl acetate/normal heptane crystallization, obtains white solid 25g, as target product after drying.Yield 96.4%, purity>99%.
Embodiment 4 (S)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- amido propionic aldehyde
In the round-bottomed flask of 1L, 105g (S)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- aminopropanols are dissolved in
In 300mL acetonitriles, under stirring, 90g IBX are added.After adding, reaction system is heated to into 50-55 DEG C, reacts 2 hours left sides
Right monitoring to raw material disappears, and reaction system is cooled down to into room temperature.Filter, filter cake 50mL acetonitrile drip washing, filter cake is made after collecting
For 2- iodosobenzoic acids, for follow-up recovery, after filtrate reduced in volume, crystallized with ethyl acetate/normal heptane, after drying
Obtain white solid 92g, as target product.Yield 88%, purity>98%.
Embodiment 5 (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- amido propionic aldehyde
In the round-bottomed flask of 1L, 105g (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- aminopropanols are dissolved in
In 800mL toluene, under stirring, 144g IBX are added.After adding, reaction system is heated to into 110 DEG C of backflows, reaction 1 is little
When or so monitor to raw material disappear, reaction system is cooled down to into room temperature.Filter, filter cake 50mL toluene drip washing, filter cake is collected
Afterwards as 2- iodosobenzoic acids, for follow-up recovery, after filtrate reduced in volume, with ethyl acetate/normal heptane crystallization, dry
White solid 89g, as target product are obtained after dry.Yield 85%, purity>99%.
Embodiment 6 (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- amido propionic aldehyde
In the round-bottomed flask of 1L, 105g (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- aminopropanols are dissolved in
In 400mL DME, under stirring, 100g IBX are added.After adding, reaction system is heated to into 30～35 DEG C, is reacted 3 hours
Left and right monitors to raw material and disappears, and reaction system is cooled down to into room temperature.Filter, filter cake 50mL DME drip washing, after filter cake is collected
As 2- iodosobenzoic acids, for follow-up recovery, after filtrate reduced in volume, with ethyl acetate/normal heptane crystallization, drying
After obtain white solid 97g, as target product.Yield 93%, purity>99%.
Embodiment 7 (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- amido propionic aldehyde
In the round-bottomed flask of 1L, 105g (R)-N-Boc-3- (1,1 '-biphenyl -4- bases) -2- aminopropanols are dissolved in
In 1200mL toluene, under stirring, 180g IBX are added.After adding, reaction system is heated to into 90-95 DEG C, is reacted 1 hour
Left and right monitors to raw material and disappears, and reaction system is cooled down to into room temperature.Filter, filter cake 50mL toluene drip washing, after filter cake is collected
As 2- iodosobenzoic acids, for follow-up recovery, after filtrate reduced in volume, with ethyl acetate/normal heptane crystallization, drying
After obtain white solid 90g, as target product.Yield 86%, purity>98%.
Claims (10)
1. a kind of preparation method of the ammonium aldehyde of N-Boc- biphenyl third, it comprises the steps：In organic solvent, by N-Boc- biphenyl
Propanolamine and 2- iodosobenzoic acids carry out oxidation reaction, obtain the ammonium aldehyde of N-Boc- biphenyl third；
Wherein, " * " in described N-Boc- biphenyl Propanolamine and the described ammonium aldehyde of N-Boc- biphenyl third represents that the carbon of mark is former
Son is asymmetric carbon atom, and its configuration is identical.
2. preparation method as claimed in claim 1, it is characterised in that described N-Boc- biphenyl Propanolamine and described N-
The ammonium aldehyde of Boc- biphenyl third is simultaneously R configurations, S configurations or, the mixture of R configurations and S configurations；
And/or, in described oxidation reaction, described organic solvent is nitrile solvents, aromatic hydrocarbon solvent and ether solvent
In one or more；
And/or, in described oxidation reaction, the volume mass of described organic solvent and described N-Boc- biphenyl Propanolamines
Than for 3～12mL/g；
And/or, in described oxidation reaction, described 2- iodosobenzoic acids rub with described N-Boc- biphenyl Propanolamines
You are than being 1.0～2.0；
And/or, the temperature of described oxidation reaction is 30～120 DEG C；
And/or, described oxidation reaction no longer reacts the terminal as reaction using N-Boc- biphenyl Propanolamine.
3. preparation method as claimed in claim 2, it is characterised in that in described oxidation reaction, described nitrile solvents
For acetonitrile；
And/or, in described oxidation reaction, described aromatic hydrocarbon solvent is toluene；
And/or, in described oxidation reaction, described ether solvent is 1,2- dimethoxy-ethanes；
And/or, in described oxidation reaction, the volume mass of described organic solvent and described N-Boc- biphenyl Propanolamines
Than for 4～8mL/g；
And/or, in described oxidation reaction, described 2- iodosobenzoic acids rub with described N-Boc- biphenyl Propanolamines
You are than being 1.1～1.6；
And/or, the temperature of described oxidation reaction is 50～90 DEG C.
4. preparation method as claimed in claim 3, it is characterised in that in described oxidation reaction, described organic solvent
It is 5～6mL/g with the volume mass ratio of described N-Boc- biphenyl Propanolamines；
And/or, in described oxidation reaction, described 2- iodosobenzoic acids rub with described N-Boc- biphenyl Propanolamines
You are than being 1.3～1.4；
And/or, the temperature of described oxidation reaction is 75～85 DEG C.
5. preparation method as claimed in claim 1, it is characterised in that described oxidation reaction also includes following post processing steps
Suddenly：Cooling, filters, and with described organic solvent washing filter cake, filtrate concentration, recrystallization obtains described N-Boc- biphenyl third
Ammonium aldehyde.
6. preparation method as claimed in claim 5, it is characterised in that described cooling is to be down to room temperature；
And/or, the solvent that described recrystallization is used is ethyl acetate and normal heptane.
7. preparation method as claimed in claim 5, it is characterised in that the post-processing step of described oxidation reaction, also includes
Following step：In water, described filter cake and oxidant are carried out into oxidation reaction, obtain 2- iodosobenzoic acids.
8. preparation method as claimed in claim 7, it is characterised in that in the preparation method of described 2- iodosobenzoic acids
In, described oxidant is potassium permanganate or potassium hydrogen persulfate；
And/or, in the preparation method of described 2- iodosobenzoic acids, the mol ratio of described oxidant and described filter cake
For 2.0～3.6；
And/or, in the preparation method of described 2- iodosobenzoic acids, the temperature of described oxidation reaction is 30～100 DEG C；
And/or, in the preparation method of described 2- iodosobenzoic acids, described oxidation reaction is with 2- iodosobenzoic acids
Residual is less than 2% as the terminal of reaction.
9. preparation method as claimed in claim 8, it is characterised in that in the preparation method of described 2- iodosobenzoic acids
In, described oxidant is potassium hydrogen persulfate；
And/or, in the preparation method of described 2- iodosobenzoic acids, the mol ratio of described oxidant and described filter cake
For 2.7～3.0；
And/or, in the preparation method of described 2- iodosobenzoic acids, the temperature of described oxidation reaction is 50～90 DEG C.
10. preparation method as claimed in claim 9, it is characterised in that in the preparation method of described 2- iodosobenzoic acids
In, the temperature of described oxidation reaction is 65～75 DEG C.
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