CN106674031A - Preparation method of R-2-dihydroindenyl glycine - Google Patents
Preparation method of R-2-dihydroindenyl glycine Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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Abstract
The invention discloses a novel method for preparing R-2-dihydroindenyl glycine. The preparation method comprises the following steps of making 2-dihydroindenyl aldehyde, D-phenylglycinol and trimethylsilyl cyanide subjected to an asymmetric cyanosilylation reaction under the action of a catalyst A, and afterwards, making a first reaction product subjected to post treatment to obtain a compound I shown by a formula (I); hydrolyzing the compound I shown by the formula (I) in an acidic condition, making a second reaction product subjected to post treatment to obtain a compound II shown by a formula II; afterwards, making the compound II shown by the formula (II) subjected to a catalytic hydrogenation reaction to obtain the R-2-dihydroindenyl glycine shown by a formula (III). Cheap and easily-obtained organic raw materials are utilized for the novel method; the preparation method has the advantages of being mild in reaction conditions, being simple and convenient to operate, being high in atomic utilization rate, being environment-friendly and being low in production cost, and the like.
Description
Technical field
The present invention relates to have the Retosiban of the antagonist action of effective as selective crucial middle to ocytocin receptor
The novel preparation method of body R-2- indane propylhomoserins.
Background technology
In the U.S., there are 4,000,000 neonates to be born every year, wherein have 500,000~1,000,000 anemia of pregnant woman needing with anti-premature labor medicine
Thing prevention of preterm birth, the sales volume of the annual anti-premature labor medicine in the U.S. is about 500,000,000 dollars.In Europe, about 8,000,000 new lives every year
Youngster is born, it is contemplated that 2,000,000~3,000,000 anemia of pregnant woman is needed using the treatment of anti-premature labor medicine.US and European is global maximum
Anti- premature labor pharmaceutical market, year, market scale was more than 1,000,000,000 Euros.In 20,000,000 neonates that China is born every year, premature infant reaches
To 2,000,000.Chinese premature labor accounts for the 5%~15% of childbirth sum, and about 15% premature infant is dead in neonatal period.Premature infant is not only
Family burden is increased, a succession of social problem is also brought.Premature infant becomes a difficult problem for World Focusing, clinical application
Demand is a huge driving for the research and development of anti-premature labor medicine.
Hormone oxytocin is effective uterotonic and for inducing or strengthening childbirth.The density of uterine oxytocin receptors
More than 100 times are significantly enhanced in gestation, and are to peak in childbirth.Antenatal childbirth causes about 60% fetus
Mortality rate/sickness rate, therefore suppress the compound of the uterus effect of oxytocin, such as oxytocin antagonist, it should to antenatal childbirth
Prevention or control it is very helpful.Clinical research confirmation, the incidence and mortality of premature infant is closely related with pregnant age, with pregnant
The increase in age, the incidence and mortality related to premature labor is substantially reduced.Premature infant of the pregnant age less than 28 weeks, often postpones to go out for 1 day
Raw neonate, its survival rate can improve 3%.Thus tocolytic agent is medicine most-often used in anti-premature labor medicine.
Retosiban is the selectivity oxytocin antagonist that Treatment of Preterm Labor is developed for by GlaxoSmithKline PLC, except vein note
Penetrate outside dosage form, Retosiban also has oral tablet and the various dosage forms of oral solution, current Retosiban Bulgaria,
Colombia, France, Singapore, Korea, Spain, Britain and the U.S. carry out the II phase clinical research for treating premature labor.R-
2- indane propylhomoserins are the important chiral intermediates for synthesizing Retosiban, belong to a kind of non-natural chiralα-aminoacid.
At present only United States Patent (USP) US8357685 reports the synthetic method of R-2- indane propylhomoserins.The method with indenes and
Chiral nitrone is raw material, and Jing 1,3- Dipolar Cycloaddition, catalytic hydrogenation are obtained R-2- indane propylhomoserins.The method is raw materials used
Chiral nitrone is difficult to obtain, and the stereo selectivity of cycloaddition reaction is relatively low, and reaction yield is low, and step is relatively complicated, uncomfortable
Together in industrialized production.
Strecker reactions are to synthesize the most classical method of a-amino acid, i.e., imines asymmetric addition is obtained by cyano group
Amino nitrile intermediates, then Jing hydrolysis prepare a-amino acid.But traditional Strecker reactions use Cyanogran. or potassium cyanide
For cyanating reagent, because the reagent is poisonous reagent, not only there is very big potential safety hazard in production, operation has high demands, and
Environmental pollution is serious.
Therefore, a kind of efficient, environment amenable R-2- indanes propylhomoserin preparation method is developed particularly important.
The content of the invention
The present invention utilizes Organic Ingredientss cheap and easy to get, under condition of no solvent, three components " one kettle way " of magnesium catalysis
Asymmetric cyanosilylation reacts to construct the spatial chemistry of R-2- indane propylhomoserins with high selectivity, there is provided one kind prepares R-2- dihydros
The new method of indenes propylhomoserin.
A kind of new method for preparing R-2- indane propylhomoserins, methods described is carried out as follows：
(a) by 2- indane aldehyde, the sweet amine alcohol of D- benzene and trimethylsilyl cyanide in the presence of catalyst A, at 0~70 DEG C
1~8h of reaction, the post-treated compounds I obtained shown in formula I of gained reactant mixture；Described catalyst A is diiodinating
Magnesium, dibrominated magnesium, magnesium dichloride, magnesium perchlorate or trifluoromethanesulfonic acid magnesium；Described 2- indane aldehyde, D- benzene glycinols, front three
The ratio of the amount of the material of base cyanogen silane and catalyst A is 1：1.0~1.5：1.0~2.0：0.1~0.5；
B () mixes the compounds I shown in step (a) gained formula I with acid, heating 1~10h at 30~120 DEG C is carried out
Acidic hydrolysises, the purified process of gained product obtains the compound ii shown in formula II；Compound shown in the formula I
I is 1 with the ratio of the amount of the material of acid：1.5~4.5；
C () is dissolved in the compound ii shown in step (b) gained formula II in organic solvent, add catalyst B, 40~
60 DEG C, 4~12h is reacted under normal pressure, Filtration of catalyst B obtains the R-2- indane propylhomoserins shown in formula III；Described urges
Agent B is palladium dydroxide, palladium carbon or Raney's nickel；The quality of the catalyst B is the compound ii quality shown in formula II
0.01~0.2g/g compound iis.
Further, in step (a), the preferably reaction condition is：Temperature is 20~40 DEG C, and the time is 2~5h.
Further, in step (a), preferred the 2- indanes aldehyde, D- benzene glycinols, trimethylsilyl cyanide and catalyst A
Material amount ratio be 1：1.1：1.2：0.1.
Further, in step (a), preferably described catalyst A is magnesium diiodide or dibrominated magnesium；It is most preferably diiodinating
Magnesium.
Further, in step (a), the post-processing approach of the reactant mixture is：After reaction terminates, to reaction mixing
Na is added in thing2S2O3Aqueous solution is quenched reaction, is extracted by ethyl acetate, takes extract, with saturated common salt water washing, anhydrous
Sodium sulfate is dried, concentration, with PE：EA=2:1, as mobile phase Jing column chromatography for separation, collects containing the compounds I shown in formula I
Eluent, is evaporated off the compounds I that solvent obtains shown in formula I.
Further, in step (b), described acid is hydrochloric acid, hydrobromic acid, sulphuric acid or acetic acid.
Further, in step (b), the preferably described temperature being heated to reflux is 80~110 DEG C, and the time is 4~6h.
Further, in step (b), the compounds I preferably shown in the formula I is 1 with the ratio of the amount of the material of acid：3.0
~4.0.
Further, in step (b), described acid is added in the form of aqueous acid, described aqueous acid quality
Concentration is 3.8%~10% aqueous solution.
Further, in step (b), the purification treating method of product is：After reaction terminates, sodium hydroxide water is added
Solution adjusts pH=4-5, and the extraction of Jing ethyl acetate takes extract layer drying, the compound ii being concentrated to give shown in formula II.
Further, in step (c), when described catalyst B is palladium dydroxide or palladium carbon, preferred palladium content is 5~10%；
Further, in step (c), when described catalyst B is Raney's nickel, preferred nickel content is 80~90%.
Further, in step (c), preferably the quality of the catalyst B be the compound ii quality shown in formula II 1~
20%；Further, preferably 1~10%, more preferably 3~5%.
Further, in step (c), described organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, acetic acid first
One kind or arbitrarily several mixing in ester, propyl acetate, butyl acetate, tetrahydrofuran, 2- methyltetrahydrofurans.
Further, in step (c), the addition of described organic solvent is with the quality of the compound ii shown in formula (2)
It is calculated as 2.1~4.3mL/g.
Compared with prior art, beneficial effects of the present invention are：
(1) using cheap and environmentally friendly catalyst lewis acidity magnesium catalysis 2- indane aldehyde, D- benzene glycinol and
The silicon cyanation of TMSCN prepares R-2- indane propylhomoserins, the stereo selectivity with height, it is not necessary to low temperature and anhydrous, nothing
The harsh operating condition such as oxygen；
(2) poisonous reagent Cyanogran. or potassium cyanide are substituted using the third level natural division of low toxicity, safety, is improve in production
Safety, reduces environmental pollution.
(3) have the advantages that reaction condition is gentle, easy to operate, atom utilization is high, environmental friendliness, low production cost,
It is a kind of new method for preparing R-2- indane propylhomoserins.
(4) use of organic solvent is avoided from source, it then follows Green Chemistry principle, realizes that " one kettle way " is asymmetric
Streck reacts, and obtains the R-2- indane propylhomoserins of highly-solid selectively.
Specific embodiment
Below by specific embodiment, technical scheme is described in further detail；But the present invention is not
It is limited to these embodiments.
The synthesis of the compound I of embodiment 1
Add dry 100mL mono- 2- indane aldehyde (14.6g, 0.1mol) and the sweet amine alcohol of D- benzene (13.7g, 0.1mol)
In mouth flask, under the protection of nitrogen, MgI is added2(10mmol), stir and TMSCN (9.9g, 0.1mol), room are added after 10min
The lower stirring reaction of temperature, TLC detection reaction process, coreaction 4.5h, reaction adds Na after terminating2S2O3Aqueous solution is quenched reaction, second
Acetoacetic ester is extracted, and takes extract, with saturated common salt water washing, anhydrous sodium sulfate drying, concentration, with petroleum ether:Ethyl acetate=
2:1 obtains amino nitrile compounds (26.29g, 0.09mol), yield 91% as eluant Jing column chromatography for separation.H NMR
(500MHz,CDCl3) δ 2.80-3.06 (m, 4H), 3.57-3.67 (m, 1H), 3.76 (dd, J=4.0,8.0Hz, 1H), 4.06-
4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H), 7.29-7.41 (m, 9H).
The synthesis of the compound I of embodiment 2
2- indane aldehyde (17.53g, 0.12mol) and the sweet amine alcohol of D- benzene (20.56g, 0.15mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium diiodide (30mmol) is added, after stirring 10min TMSCN is added
(14.286g, 0.144mol), stirring reaction under room temperature, TLC detection reaction process, coreaction 4.2h, reaction is added after terminating
Na2S2O3Aqueous solution is quenched reaction, and ethyl acetate extraction takes extract, dense with saturated common salt water washing, anhydrous sodium sulfate drying
After contracting, with petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (32.96g,
0.112mol), yield 94%.H NMR(500MHz,CDCl3)δ2.80-3.06(m, 4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of embodiment 3
2- indane aldehyde (20.45g, 0.14mol) and the sweet amine alcohol of D- benzene (21.11g, 0.154mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium diiodide (14mmol) is added, after stirring 10min TMSCN is added
(16.632g, 0.168mol), stirring reaction under room temperature, TLC detection reaction process, coreaction 4.5h, reaction is added after terminating
Na2S2O3Aqueous solution is quenched reaction, and ethyl acetate extraction takes extract, dense with saturated common salt water washing, anhydrous sodium sulfate drying
After contracting, with petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (37.98g,
0.13mol), yield 95%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of embodiment 4
2- indane aldehyde (17.53g, 0.12mol) and the sweet amine alcohol of D- benzene (24.07g, 0.18mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium diiodide (60mmol) is added, after stirring 10min TMSCN is added
(23.76g, 0.24mol), stirring reaction under room temperature, TLC detection reaction process, coreaction 4.5h, reaction is added after terminating
Na2S2O3Aqueous solution is quenched reaction, and ethyl acetate extraction takes extract, dense with saturated common salt water washing, anhydrous sodium sulfate drying
After contracting, with petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (32.13g,
0.11mol), yield 91%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of embodiment 5
2- indane aldehyde (21.91g, 0.15mol) and the sweet amine alcohol of D- benzene (22.62g, 0.165mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium diiodide (15mmol) is added, after stirring 10min TMSCN is added
(17.83g, 0.18mol), stirring reaction at 0 DEG C, TLC detection reaction process, coreaction 6h, reaction adds Na after terminating2S2O3
Aqueous solution is quenched reaction, ethyl acetate extraction, takes extract, with saturated common salt water washing, anhydrous sodium sulfate drying, after concentration,
With petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (39.44g,
0.135mol), yield 90%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of embodiment 6
2- indane aldehyde (20.45g, 0.14mol) and the sweet amine alcohol of D- benzene (21.11g, 0.154mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium diiodide (14mmol) is added, after stirring 10min TMSCN is added
(16.632g, 0.168mol), stirring reaction at 70 DEG C, TLC detection reaction process, coreaction 3.6h, reaction is added after terminating
Na2S2O3Aqueous solution is quenched reaction, and ethyl acetate extraction takes extract, dense with saturated common salt water washing, anhydrous sodium sulfate drying
After contracting, with petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (36.4g,
0.125mol), yield 89%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of embodiment 7
2- indane aldehyde (17.53g, 0.12mol) and the sweet amine alcohol of D- benzene (18.09g, 0.132mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium diiodide (12mmol) is added, after stirring 10min TMSCN is added
(14.26g, 0.144mol), stirring reaction under room temperature adds Na after reaction 1h2S2O3Aqueous solution is quenched reaction, ethyl acetate extraction
Take, take extract, with saturated common salt water washing, anhydrous sodium sulfate drying, after concentration, with petroleum ether:Ethyl acetate=2:1 conduct
Eluant Jing column chromatography for separation obtains amino nitrile compounds (26.93g, 0.092mol), yield 70%.H NMR(500MHz,
CDCl3) δ 2.80-3.06 (m, 4H), 3.57-3.67 (m, 1H), 3.76 (dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m,
1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H), 7.29-7.41 (m, 9H).
The synthesis of the compound I of embodiment 8
2- indane aldehyde (29.21g, 0.2mol) and the sweet amine alcohol of D- benzene (30.16g, 0.22mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium diiodide (20mmol) is added, after stirring 10min TMSCN is added
(23.77g, 0.24mol), stirring reaction under room temperature adds Na after 8h2S2O3Aqueous solution is quenched reaction, and ethyl acetate extraction takes
Extract, with saturated common salt water washing, anhydrous sodium sulfate drying, after concentration, with petroleum ether:Ethyl acetate=2:1 used as eluting
Agent Jing column chromatography for separation obtains amino nitrile compounds (43.82g, 0.15mol), yield 75%.H NMR(500MHz,CDCl3)δ
2.80-3.06 (m, 4H), 3.57-3.67 (m, 1H), 3.76 (dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24
(dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H), 7.29-7.41 (m, 9H).
The synthesis of the compound I of the dibrominated magnesium of embodiment 9 catalysis
2- indane aldehyde (21.91g, 0.15mol) and the sweet amine alcohol of D- benzene (22.6g, 0.165mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, dibrominated magnesium (2.76g, 15mmol) is added, added after stirring 10min
TMSCN (17.8g, 0.18mol), stirring reaction under room temperature, TLC detection reaction process, coreaction 6.2h, reaction is added after terminating
Na2S2O3Aqueous solution is quenched reaction, and ethyl acetate extraction takes extract, dense with saturated common salt water washing, anhydrous sodium sulfate drying
After contracting, with petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (38.56g,
0.132mol), yield 88%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of the magnesium dichloride of embodiment 10 catalysis
2- indane aldehyde (24.83g, 0.17mol) and the sweet amine alcohol of D- benzene (25.62g, 0.187mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium dichloride (1.62g, 17mmol) is added, added after stirring 10min
TMSCN (20.24g, 0.204mol), stirring reaction under room temperature, TLC detection reaction process, coreaction 5.5h, reaction adds after terminating
Enter Na2S2O3Aqueous solution is quenched reaction, ethyl acetate extraction, takes extract, with saturated common salt water washing, anhydrous sodium sulfate drying,
After concentration, with petroleum ether:Ethyl acetate=2:1 as mobile phase Jing column chromatography for separation obtain amino nitrile compounds (39.73g,
0.136mol), yield 80%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of the trifluoromethanesulfonic acid magnesium of embodiment 11 catalysis
2- indane aldehyde (29.2g, 0.2mol) and the sweet amine alcohol of D- benzene (30.14g, 0.22mol) are added into dry 100mL
In single-necked flask, under the protection of nitrogen, trifluoromethanesulfonic acid magnesium (6.45g, 0.02mol) is added, added after stirring 10min
TMSCN (23.81g, 0.24mol), stirring reaction under room temperature, TLC detection reaction process, coreaction 5h, reaction is added after terminating
Na2S2O3Aqueous solution is quenched reaction, and ethyl acetate extraction takes extract, dense with saturated common salt water washing, anhydrous sodium sulfate drying
After contracting, with petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (43.82g,
0.15mol), yield 75%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The synthesis of the compound I of the magnesium perchlorate of embodiment 12 catalysis
2- indane aldehyde (23.3g, 0.16mol) and the sweet amine alcohol of D- benzene (24.12g, 0.176mol) are added into drying
In 100mL single-necked flasks, under the protection of nitrogen, magnesium perchlorate (3.57g, 16mmol) is added, added after stirring 10min
TMSCN (17.82g, 0.18mol), stirring reaction under room temperature, TLC detection reaction process, coreaction 4.8h, reaction adds after terminating
Enter Na2S2O3Aqueous solution is quenched reaction, ethyl acetate extraction, takes extract, with saturated common salt water washing, anhydrous sodium sulfate drying,
After concentration, with petroleum ether:Ethyl acetate=2:1 as eluant Jing column chromatography for separation obtain amino nitrile compounds (35.53g,
0.121mol), yield 76%.H NMR(500MHz,CDCl3)δ2.80-3.06(m,4H),3.57-3.67(m,1H),3.76
(dd, J=4.0,8.0Hz, 1H), 4.06-4.12 (m, 1H), 4.24 (dd, J=4.0,10.9Hz, 1H), 4.58 (s, 1H),
7.29-7.41(m,9H).
The preparation of the compound ii of embodiment 13
Amino nitrile compounds (26.29g, 0.09mol) prepared by embodiment 1, the aqueous sulfuric acid (sulphuric acid of 500mL 5%
Common 0.26mol) it is heated to reflux 4 hours at 90 DEG C, adjust pH=4.5 with 1.0mol/L sodium hydrate aqueous solutions, ethyl acetate extraction,
Extract drying is taken, hydrolyzate (24.36g, 0.078mol), yield 87% is concentrated to give.H NMR(500MHz,CDCl3)δ
2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33
(dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 14
Amino nitrile compounds (32.96g, 0.112mol) prepared by embodiment 2, the aqueous sulfuric acid (sulfur of 500mL 9.8%
The common 0.504mol of acid) 90 DEG C be heated to reflux 4 hours, adjust pH=4.5, ethyl acetate to extract with 1.0mol/L sodium hydrate aqueous solutions
Take, take extract drying, be concentrated to give hydrolyzate (27.88g, 0.09mol), yield 80%.H NMR(500MHz,CDCl3)
δ 2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H),
4.33 (dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 15
Amino nitrile compounds (37.98g, 0.13mol) prepared by embodiment 3, the aqueous sulfuric acid (sulfur of 500mL 3.8%
The common 0.195mol of acid) 90 DEG C be heated to reflux 4 hours, adjust pH=4.5, ethyl acetate to extract with 1.0mol/L sodium hydrate aqueous solutions
Take, take extract drying, be concentrated to give hydrolyzate (34.38g, 0.11mol), yield 85%.H NMR(500MHz,CDCl3)
δ 2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H),
4.33 (dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 16
Amino nitrile compounds (32.13g, 0.11mol) prepared by embodiment 4, the aqueous sulfuric acid (sulphuric acid of 500mL 8%
Common 0.4mol) 90 DEG C be heated to reflux 4 hours, adjust pH=4.5, ethyl acetate extraction to take with 1.0mol/L sodium hydrate aqueous solutions
Extract is dried, and is concentrated to give hydrolyzate (31.48g, 0.10mol), yield 92%.H NMR(500MHz,CDCl3)δ
2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33
(dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 17
Amino nitrile compounds (39.44g, 0.135mol) prepared by embodiment 5, the aqueous sulfuric acid (sulfur of 500mL 10%
The common 0.54mol of acid) 90 DEG C be heated to reflux 4 hours, adjust pH=4.5, ethyl acetate to extract with 1.0mol/L sodium hydrate aqueous solutions,
Extract drying is taken, hydrolyzate (37.43g, 0.12mol), yield 89% is concentrated to give.H NMR(500MHz,CDCl3)δ
2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33
(dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 18
Amino nitrile compounds (36.4g, 0.125mol) prepared by embodiment 6, the aqueous sulfuric acid (sulphuric acid of 500mL 9%
Common 0.46mol) 30 DEG C of heating 4 hours, adjust pH=4.5, ethyl acetate extraction to take extraction with 1.0mol/L sodium hydrate aqueous solutions
Liquid is dried, and is concentrated to give hydrolyzate (29.21g, 0.094mol), yield 75%.H NMR(500MHz,CDCl3)δ2.75-
3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33 (dd, J
=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 19
Amino nitrile compounds (26.93g, 0.092mol) prepared by embodiment 7, the aqueous sulfuric acid (sulphuric acid of 500mL 6%
Common 0.30mol) 120 DEG C be heated to reflux 4 hours, adjust pH=4.5 with 1.0mol/L sodium hydrate aqueous solutions, ethyl acetate extraction,
Extract drying is taken, hydrolyzate (23.22g, 0.075mol), yield 81% is concentrated to give.H NMR(500MHz,CDCl3)δ
2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33
(dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 20
Amino nitrile compounds (43.82g, 0.15mol) prepared by embodiment 8,500mL10% aqueous sulfuric acid (sulphuric acid
Common 0.51mol) 90 DEG C be heated to reflux 1 hour, adjust pH=4.5, ethyl acetate extraction to do with 1.0mol/L sodium hydrate aqueous solutions
It is dry, it is concentrated to give hydrolyzate (34.27g, 0.11mol), yield 73%.H NMR(500MHz,CDCl3)δ2.75-3.02(m,
4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33 (dd, J=4.0,
10.9Hz,1H),4.68(s,1H),7.35-7.51(m,9H).
The preparation of the compound ii of embodiment 21
Amino nitrile compounds (38.56g, 0.132mol) prepared by embodiment 9, the aqueous sulfuric acid (sulphuric acid of 500mL 9%
Common 0.46mol) 90 DEG C be heated to reflux 10 hours, adjust pH=4.5 with 1.0mol/L sodium hydrate aqueous solutions, ethyl acetate extraction,
Extract drying is taken, hydrolyzate (34.96g, 0.112mol), yield 85% is concentrated to give.H NMR(500MHz,CDCl3)δ
2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33
(dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 22
Amino nitrile compounds (39.73g, 0.136mol) prepared by embodiment 10, the hydrobromic acid aqueous solutions of 500mL 8%
90 DEG C of (the common 0.49mol of hydrogen bromide) is heated to reflux 4 hours, and with 1.0mol/L sodium hydrate aqueous solutions pH=4.5, ethyl acetate are adjusted
Extraction, takes extract drying, is concentrated to give hydrolyzate (33.90g, 0.109mol), yield 80%.H NMR(500MHz,
CDCl3) δ 2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m,
1H), 4.33 (dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
The preparation of the compound ii of embodiment 23
Amino nitrile compounds (43.82g, 0.15mol) prepared by embodiment 11, the aqueous acetic acid (acetic acid of 500mL 6%
Common 0.5mol) 90 DEG C be heated to reflux 4 hours, adjust pH=4.5, ethyl acetate extraction to take with 1.0mol/L sodium hydrate aqueous solutions
Extract is dried, and is concentrated to give hydrolyzate (38.32g, 0.123mol), yield 82%.H NMR(500MHz,CDCl3)δ
2.75-3.02 (m, 4H), 3.53-3.57 (m, 1H), 3.66 (dd, J=4.0,8.0Hz, 1H), 4.10-4.20 (m, 1H), 4.33
(dd, J=4.0,10.9Hz, 1H), 4.68 (s, 1H), 7.35-7.51 (m, 9H).
It is prepared by the R-2- indanes propylhomoserin of embodiment 24
Hydrolyzate (24.36g, 0.078mol) prepared by embodiment 13 is dissolved in methanol (100ml), adds 2g matter
Amount fraction be 10% palladium-carbon (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst,
It is concentrated to give R-2- indane propylhomoserins (12.37g, 0.0647mol), yield 83%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 25
Hydrolyzate (34.38g, 0.11mol) prepared by embodiment 15 is dissolved in methanol (100ml), adds 0.35g matter
Amount fraction be 10% palladium-carbon (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst,
It is concentrated to give R-2- indane propylhomoserins (11.93g, 0.0624mol), yield 80%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 26
Hydrolyzate (31.48g, 0.10mol) prepared by embodiment 16 is dissolved in methanol (100ml), adds 1.26g matter
Amount fraction be 10% palladium-carbon (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst,
It is concentrated to give R-2- indane propylhomoserins (16.83g, 0.088mol), yield 88%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 27
Hydrolyzate (37.43g, 0.12mol) prepared by embodiment 17 is dissolved in methanol (100ml), adds 7.5g matter
Amount fraction be 10% palladium-carbon (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst,
It is concentrated to give R-2- indane propylhomoserins (18.12g, 0.095mol), yield 79%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),
3.06-2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 28
Hydrolyzate (29.21g, 0.094mol) prepared by embodiment 18 is dissolved in methanol (100ml), adds 10.22g
Mass fraction is that (aqueous 50%), hydrogenation reaction 12 hours, are filtered to remove and urge under 50 DEG C, condition of normal pressure for 10% palladium dydroxide
Agent, is concentrated to give R-2- indane propylhomoserins (15.44g, 0.081mol), yield 86%.LC-MS m/z 192[M+H]+,1H
NMR(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),
3.06-2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 29
Hydrolyzate (23.22g, 0.075mol) prepared by embodiment 19 is dissolved in methanol (100ml), adds 0.93g
Mass fraction is that (aqueous 50%), hydrogenation reaction 12 hours under 40 DEG C, condition of normal pressure, is filtered to remove catalysis for 10% palladium-carbon
Agent, is concentrated to give R-2- indane propylhomoserins (11.61g, 0.061mol), yield 81%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 30
Hydrolyzate (34.27g, 0.11mol) prepared by embodiment 20 is dissolved in methanol (100ml), adds 1.3708g
Mass fraction is that (aqueous 50%), hydrogenation reaction 12 hours under 60 DEG C, condition of normal pressure, is filtered to remove catalysis for 10% palladium-carbon
Agent, is concentrated to give R-2- indane propylhomoserins (11.61g, 0.061mol), yield 81%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 31
Hydrolyzate (34.96g, 0.112mol) prepared by embodiment 21 is dissolved in methanol (100ml), adds 1.4g matter
Amount fraction be 10% palladium-carbon (aqueous 50%), hydrogenation reaction 4 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst,
It is concentrated to give R-2- indane propylhomoserins (16.69g, 0.087mol), yield 78%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 32
Hydrolyzate (33.90g, 0.109mol) prepared by embodiment 22 is dissolved in methanol (100ml), adds 1.356g
Mass fraction is 85% Raney's nickel (commercially available, Jiangsu Jingjiang City Hong Peng catalyst company limited, model:RC-2L), 50 DEG C,
Hydrogenation reaction 12 hours, Filtration of catalyst under condition of normal pressure, be concentrated to give R-2- indane propylhomoserins (17.77g,
0.093mol), yield 85%.LC-MS m/z 192[M+H]+,1H NMR(DMSO-d6)δ8.42-8.32(br s,3H),
7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 33
Hydrolyzate (38.32g, 0.123mol) prepared by embodiment 23 is dissolved in ethanol (100ml), adds 1.532g
Mass fraction is that (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, is filtered to remove catalysis for 10% palladium-carbon
Agent, is concentrated to give R-2- indane propylhomoserins (17.77g, 0.093mol), yield 85%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 34
Hydrolyzate compound ii (40g, 0.128mol) is dissolved in isopropanol (100ml), 1.6g mass fractions are added
For 10% palladium-carbon, (aqueous 50%), hydrogenation reaction 12 hours, Filtration of catalyst, are concentrated to give under 50 DEG C, condition of normal pressure
To R-2- indane propylhomoserins (19.81g, 0.104mol), yield 81%.LC-MS m/z 192[M+H]+,1H NMR(DMSO-d6)
δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2), 3.06-2.80(m,
5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 35
Hydrolyzate compound ii (40.5g, 0.13mol) is dissolved in ethyl acetate (100ml), 1.62g mass is added
Fraction is that (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst is dense for 10% palladium-carbon
Contracting obtains R-2- indane propylhomoserins (20.62g, 0.108mol), yield 83%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 36
Hydrolyzate compound ii (46.7g, 0.15mol) is dissolved in methyl acetate (100ml), 1.87g mass is added
Fraction is that (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst is dense for 10% palladium-carbon
Contracting obtains R-2- indane propylhomoserins (24.08g, 0.126mol), yield 84%.LC-MS m/z 192[M+H]+,1H NMR
(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-
2.80(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 37
Hydrolyzate compound ii (40g, 0.128mol) is dissolved in propyl acetate (100ml), 1.8g mass point is added
Number is 10% palladium-carbon (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst, concentration
Obtain R-2- indane propylhomoserins (20.3g, 0.106mol), yield 83%.LC-MS m/z 192[M+H]+,1H NMR(DMSO-
d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-2.80
(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 38
Hydrolyzate compound ii (43.62g, 0.14mol) is dissolved in butyl acetate (100ml), 1.74g mass is added
Fraction is that (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, Filtration of catalyst is dense for 10% palladium-carbon
Contracting obtains R-2- indane propylhomoserins (21.4g, 0.112mol), yield 80%.LC-MS m/z 192[M+H]+,1H NMR(DMSO-
d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-2.80
(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 39
Hydrolyzate compound ii (44g, 0.141mol) is dissolved in tetrahydrofuran (100ml), 2g mass fractions are added
For 10% palladium-carbon, (aqueous 50%), hydrogenation reaction 12 hours, Filtration of catalyst, are concentrated to give under 50 DEG C, condition of normal pressure
To R-2- indane propylhomoserins (21.78g, 0.114mol), yield 80.8%.LC-MS m/z 192[M+H]+,1H NMR(DMSO-
d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),3.06-2.80
(m,5H,Ar(CH2)2CH).
It is prepared by the R-2- indanes propylhomoserin of embodiment 40
Hydrolyzate compound ii (42g, 0.135mol) is dissolved in 2- methyltetrahydrofurans (100ml), 1.9g is added
Mass fraction is that (aqueous 50%), hydrogenation reaction 12 hours under 50 DEG C, condition of normal pressure, is filtered to remove catalysis for 10% palladium-carbon
Agent, is concentrated to give R-2- indane propylhomoserins (20.83g, 0.109mol), yield 80.7%.LC-MS m/z 192[M+H]+,1H
NMR(DMSO-d6)δ8.42-8.32(br s,3H),7.26-7.12(m,4H,ArH),4.12-4.06(m,1H,NCHCO2),
3.06-2.80(m,5H,Ar(CH2)2CH。
Claims (10)
1. a kind of preparation method of R-2- indanes propylhomoserin, it is characterised in that methods described is carried out as follows：
A () in the presence of catalyst A, reacts 2- indane aldehyde, the sweet amine alcohol of D- benzene and trimethylsilyl cyanide at 0~70 DEG C
1~8h, the post-treated compounds I obtained shown in formula I of gained reactant mixture；Described catalyst A be magnesium diiodide, two
Magnesium bromide, magnesium dichloride, magnesium perchlorate or trifluoromethanesulfonic acid magnesium；Described 2- indane aldehyde, D- benzene glycinols, trimethyl cyanogen silicon
The ratio of the amount of the material of alkane and catalyst A is 1：1.0~1.5：1.0~2.0：0.1~0.5；
B () mixes the compounds I shown in step (a) gained formula I with acid, heating 1~10h at 30~120 DEG C carries out acidity
Hydrolysis, the purified process of gained product obtains the compound ii shown in formula II；Compounds I shown in the formula I with
The ratio of the amount of the material of acid is 1：1.5~4.5；
C () is dissolved in the compound ii shown in step (b) gained formula II in organic solvent, catalyst B is added, 40~60
DEG C, 4~12h is reacted under normal pressure, Filtration of catalyst B obtains the R-2- indane propylhomoserins shown in formula III；Described catalysis
Agent B is palladium dydroxide, palladium carbon or Raney's nickel；The quality of the catalyst B is calculated as with the compound ii quality shown in formula II
0.01~0.2g/g compound iis.
2. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (a), institute
Stating reaction condition is：Temperature is 20~40 DEG C, and the time is 2~5h.
3. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (a), institute
The ratio for stating the amount of the material of 2- indane aldehyde, D- benzene glycinols, trimethylsilyl cyanide and catalyst A is 1：1.1：1.2：0.1.
4. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (a), institute
The catalyst A for stating is magnesium diiodide or dibrominated magnesium.
5. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (a), institute
The post-processing approach for stating reactant mixture is：After reaction terminates, in reactant mixture Na is added2S2O3Aqueous solution is quenched reaction,
Extracted by ethyl acetate, take extract, with saturated common salt water washing, anhydrous sodium sulfate drying, concentration, with petroleum ether:Acetic acid
Ethyl ester=2:1, as mobile phase Jing column chromatography for separation, collects the eluent containing the compounds I shown in formula I, solvent is evaporated off and obtains
Compounds I shown in formula I.
6. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (b), institute
The acid stated is hydrochloric acid, hydrobromic acid, sulphuric acid or acetic acid.
7. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (b), institute
The acid stated is added in the form of aqueous acid, and described aqueous acid mass concentration is 3.8%~10%.
8. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (b), instead
The purification treating method for answering product is：After reaction terminates, sodium hydrate aqueous solution is added to adjust pH=4-5, Jing ethyl acetate extraction
Take, take extract layer drying, the compound ii being concentrated to give shown in formula II.
9. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (c), institute
The organic solvent stated is selected from methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, tetrahydrochysene furan
Mutter, the one kind in 2- methyltetrahydrofurans or arbitrarily several mixing.
10. the preparation method of R-2- indanes propylhomoserin as claimed in claim 1, it is characterised in that in described step (c), institute
The addition of the organic solvent stated is calculated as 2.1~4.3mL/g with the quality of the compound ii shown in formula II.
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|---|---|---|---|---|
| CN107445852A (en) * | 2017-08-24 | 2017-12-08 | 浙江工业大学 | A kind of preparation method of D indanyls glycine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997009346A1 (en) * | 1995-09-08 | 1997-03-13 | Cortech, Inc. | Des-arg9-bk antagonists |
| CN101597282A (en) * | 2003-06-24 | 2009-12-09 | 葛兰素集团有限公司 | The diketopiperazine that replaces and as the purposes of oxytocin antagonist |
| CN104557582A (en) * | 2015-01-04 | 2015-04-29 | 浙江工业大学 | Method for preparing saxagliptin intermediate |
-
2016
- 2016-11-18 CN CN201611028594.2A patent/CN106674031A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997009346A1 (en) * | 1995-09-08 | 1997-03-13 | Cortech, Inc. | Des-arg9-bk antagonists |
| CN101597282A (en) * | 2003-06-24 | 2009-12-09 | 葛兰素集团有限公司 | The diketopiperazine that replaces and as the purposes of oxytocin antagonist |
| CN104557582A (en) * | 2015-01-04 | 2015-04-29 | 浙江工业大学 | Method for preparing saxagliptin intermediate |
Non-Patent Citations (3)
| Title |
|---|
| ALAN D. BORTHWICK ET AL.: "2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists. 2. Synthesis, Chirality, and Pharmacokinetics", 《J. MED. CHEM.》 * |
| ASHOK ARASAPPAN ET AL.: "Practical and efficient method for amino acid derivatives containing β-quaternary center: Application toward synthesis of hepatitis C virus NS3 serine protease inhibitors", 《TETRAHEDRON LETTERS》 * |
| 郑勤 等: "无溶剂条件下MgI2催化的硅腈化反应研究", 《2012长三角药物化学研讨会》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107445852A (en) * | 2017-08-24 | 2017-12-08 | 浙江工业大学 | A kind of preparation method of D indanyls glycine |
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Application publication date: 20170517 |