CN1683077A - Recemizing method for alpha-aminoalcohol compounds and its catalyst - Google Patents

Abstract

The present invention discloses a kind of alpha-amino alcohol compound racemizing method and its catalyst. The catalyst has Al2O3 carrier and active component of one or several of Co, Cr, Mo, Rh, Zn, Fe, Cu, Ni, Sr, Ca and Bioavailability, with the total active component amount is 20-40 wt% of the catalyst. In a fixed bed reactor and hydrogen atmosphere, liquid or gas phase alpha-amino alcohol compound is introduced, diluted with solvent, and reacted at material feeding space velocity of 100-20000 /hr, temperature of 100-300 deg.c and pressure of 0.5-0.8 MPa. The present invention has the advantages of simple preparing process, low cost, stable activity and long service life of catalyst, high yield of the racemized product and high racemizing effect.

Description

The racemization method of α-An Jichun compounds and catalyst thereof

Technical field

The invention belongs to the racemization technology of medicine intermediate alpha-amido alcohols series compound, the racemization method and the catalyst thereof of the definite α-An Jichun compounds of saying so.

Background technology

The α-An Jichun compounds is the important medicine intermediate of a class.But for most of α-An Jichun compounds, it often has only a kind of enantiomer is that we are needed, and another kind of enantiomer does not have using value.For example: S-2-amino-1-butanols is the important intermediate of synthetic resistive connection nuclear class medicine ebutol, and R-2-amino-1-butanols does not have using value.Therefore in order to reduce production costs, need be converted into (R, S)-2-amino-1-butanols to R-2-amino-1-butanols by racemization, fractionation obtains S-2-amino-1-butanols and is used again.Relative patent report mainly contains following several pieces: US 4,096, Co, Co/Fe that 186 reports prepare with coprecipitation ₂O ₃Make catalyst, at NH ₃And H ₂Exist down R-2-amino-1-butanols is carried out racemization, its best product yield is 97.6% o'clock, and the racemization rate only is 63%; In the racemization rate is 99% o'clock, and its product yield only is 75.1%, promptly can not reach better racemization effect and higher product yield simultaneously.IN-A-162,213 report Rh/Al ₂O ₃Make catalyst, at NH ₃And H ₂Exist down R-2-amino-1-butanols is carried out racemization, but its racemization rate only has 42.5%.The common drawback of above two pieces of patents is simultaneously: one, need to use NH in reaction ₃, make to produce to be difficult to control, make the refining difficulty of product simultaneously; Two, the catalyst cost is higher.US 4,990, and 666 reports are made catalyst with the skeleton cobalt, facing the racemization that is used for R-2-amino-1-butanols under the hydrogen state, but it mainly is applicable to intermittent reaction, and the catalyst cost are higher.Therefore, the racemization research to alpha-amido alcohols series compound is necessary.

Summary of the invention

The objective of the invention is to solve the deficiencies in the prior art, a kind of racemization method and catalyst thereof of α-An Jichun compounds is provided.

The catalyst of the racemization method of α-An Jichun compounds of the present invention is with Al ₂O ₃Be carrier, active component is the simple substance of Co, Cr, Mo, Rh, Zn, Fe, Cu, Ni, Sr, Ca, Ba or the composite catalyst of multiple simple substance; Or the composite catalyst of simple substance and its oxide, the mass content of each active component is the 5%-20% of catalyst gross mass, the gross activity component content is the 20%-40% of catalyst gross mass.

Among the present invention the method for preparing catalyst that uses simple, adopt common preparation method, preferred infusion process, coprecipitation, kneading extrusion method.Improve the catalytic performance of catalyst by the compound action of active component and carrier.The preferred Mo/Co/Cr of catalyst activity component, Ni/Co/Zn, Ni/Cu/Zn, Ni/Co/Cr, Co/Cr/Fe ₂O ₃, Co/Sr/Fe ₂O ₃, Co/Ca/Fe ₂O ₃And Co/Ba/Fe ₂O ₃

The racemization method of α-An Jichun compounds of the present invention is to adopt fixed bed, feeds the α-An Jichun compounds of liquid phase or gas phase under atmosphere of hydrogen, and α-An Jichun compounds solvent dilution, solvent load are the 30-90% of reactant liquor gross mass; The charging air speed is 100-20000h ^-1, reaction temperature is 100-300 ℃, reaction pressure 0.5-8Mpa.

Reaction temperature in the above-mentioned method answers pressure preferably at 2.7-4.7MPa preferably at 170-220 ℃.

Add appropriate solvent and help the carrying out that react, experiment showed, oxolane and some solvent, for example benzene series solvent such as benzene, toluene, ether solvent such as ether, dioxane, alcohols solvent such as methyl alcohol, ethanol, water etc. can both help the carrying out that react in various degree.Solvent load is preferably the 45-75% of reactant liquor gross mass.

Alpha-amido alcohols series compound of the present invention is:

R wherein ₁Be C ₁-C ₆The straight chained alkyl or the C of low carbon number ₅-C ₈Low carbon number cycloalkyl or aryl or have substituent aryl; R ₂Be hydrogen or C ₁-C ₆The straight chained alkyl or the C of low carbon number ₅-C ₈Low carbon number cycloalkyl or aryl or have substituent aryl; R ₃Be hydrogen or C ₁-C ₆The straight chained alkyl of low carbon number.

With fixed bed the α-An Jichun compounds is carried out racemic process.This method has operating condition and is easy to control, and catalyst performance is good, the characteristics that product yield is high.And the Preparation of Catalyst of using is easy, and the catalyst cost is low, and is activity stabilized, and the life-span is long, catalysis racemization product yield height, and racemization is effective.

The specific embodiment

Further introduce technical characterstic of the present invention below by example:

Example 1: immersion process for preparing catalyst

The heating of 80g cobalt nitrate is dissolved in the 140ml deionized water, adds 100g γ-Al ₂O ₃(diameter 2-3mm bead), stir, dipping spends the night, in 110 ℃ at drying box inner drying 10h, in 550 ℃ of roasting 5h in muffle furnace, promptly get required catalyst with hydrogen reductase 12 h under 400 ℃, 2.0Mpa condition, consisting of of catalyst contains cobalt 20.9%, contains Al2O386.1%.

Example 2: coprecipitation prepares catalyst

50g nitric acid molybdenum, 80g cobalt nitrate, 55g chromic nitrate are dissolved in the 750ml deionized water, add 100g Al ₂O ₃Powder stirs, and is heated to 80 ℃, keeps temperature stabilization dropwise to splash into Na at 80 ℃ ₂CO ₃The aqueous solution leaves standstill, filters, washs to not containing Na to pH=6.5 ⁺Ion, extruded moulding, spend the night at the drying box inner drying in 110 ℃, in 550 ℃ of roasting 5h in muffle furnace, promptly get required catalyst with hydrogen reductase 12 h under 400 ℃, 2.0Mpa condition, consisting of of catalyst contains molybdenum 8.0%, contains cobalt 12.1%, contains chromium 5.3%, contains Al ₂O ₃74.6%.

Example 3: kneading extrusion method prepares catalyst

50g nickel nitrate, 80g cobalt nitrate, the heating of 60g chromic nitrate are dissolved in the 150Ml deionized water, add 100g γ-Al ₂O ₃Powder, fully be ground to fully mix, extruded moulding, spend the night at the drying box inner drying in 110 ℃, in 550 ℃ of roasting 5h in muffle furnace, promptly get required catalyst with hydrogen reductase 12 h under 400 ℃, 2.0Mpa condition, consisting of of catalyst be nickeliferous 7.5%, contain cobalt 12.0%, contain chromium 5.8%, contain Al ₂O ₃74.7%.

Example 4:

Reactor is a fixed-bed tube reactor, and internal diameter 12mm, pipe range 500mm, interior dress press the catalyst 15g of example 1 preparation.The 20% toluene solution process preheating of R-2-amino-1-butanols is with 200h ^-1Speed to enter temperature be 170 ℃ beds, Hydrogen Vapor Pressure is 2.7Mpa.Reaction result: racemization rate 90.0%, product yield 86.2%.

Example 5:

The catalyst 15g of example 2 preparations is pressed in filling in said fixing bed tubular reactor.The 30% dioxane solution process preheating of R-2-amino-1-butanols is with 500h ^-1Speed to enter temperature be 190 ℃ beds, Hydrogen Vapor Pressure is 3.0Mpa.Reaction result: racemization rate 98.6%, product yield 93.3%.

Example 6:

The catalyst 15g of example 3 preparations is pressed in filling in said fixing bed tubular reactor.30% aqueous solution process preheating of R-2-amino-1-propyl alcohol is with 300h ^-1Speed to enter temperature be 180 ℃ beds, Hydrogen Vapor Pressure is 3.5Mpa.Reaction result: racemization rate 89.6%, product yield 92.7%.

Example 7:

Filling immersion process for preparing catalyst 15g in said fixing bed tubular reactor, consisting of of catalyst contains cobalt 10%, chromium 5%, iron oxide 15%, contains Al ₂O ₃70%.The 30% tetrahydrofuran solution process preheating of R-2-amino-1-butanols is with 350h ^-1Speed to enter temperature be 200 ℃ beds, Hydrogen Vapor Pressure is 4.0MPa.Reaction result: racemization rate 93.1%, product yield 93.7%.

Example 8:

The catalyst 15g of filling kneading extrusion method preparation in said fixing bed tubular reactor, consisting of of catalyst is nickeliferous 10%, copper 10%, zinc 15%, contain Al ₂O ₃65%.The 20% toluene solution process preheating of R-2-amino-1-propyl alcohol is with 400h ^-1Speed to enter temperature be 185 ℃ beds, Hydrogen Vapor Pressure is 4.0MPa.Reaction result: racemization rate 80.2%, product yield 96.7%.

Example 9:

The catalyst 15g of filling example 2 preparations in said fixing bed tubular reactor.The 20% toluene solution process preheating of R-4-amino-3-hexanol is with 400h ^-1Speed to enter temperature be 190 ℃ beds, Hydrogen Vapor Pressure is 4.0MPa.Reaction result: racemization rate 90.2%, product yield 95.3%.

Example 10:

The catalyst 15g of filling example 2 preparations in said fixing bed tubular reactor.The 20% toluene solution process preheating of R-2-methylamino-1-butanols is with 400h ^-1Speed to enter temperature be 175 ℃ beds, Hydrogen Vapor Pressure is 4.0MPa.Reaction result: racemization rate 92.3%, product yield 97.6%.

Example 11:

The catalyst 15g of filling example 2 preparations in said fixing bed tubular reactor.The 20% toluene solution process preheating of R-2-amino-phenyl butanols is with 400h ^-1Speed to enter temperature be 190 ℃ beds, Hydrogen Vapor Pressure is 4.0MPa.Reaction result: racemization rate 87.2%, product yield 94.8%.

Example 12: the catalyst 15g of filling example 2 preparations in said fixing bed tubular reactor.The 20% toluene solution process preheating of R-2-methylamino-phenyl butanols is with 400h ^-1Speed to enter temperature be 190 ℃ beds, Hydrogen Vapor Pressure is 4.0MPa.Reaction result: racemization rate 90.2%, product yield 91.3%.

Example 13:

By above-mentioned example 5 selected catalyst and reaction condition, life of catalyst is investigated, the results are shown in Table 1.

Table: 1 life of catalyst experimental result

Reaction time (h)	????10	????30	????80	????150	??300	??500	??1000
								Product yield (%)	????93.3	????94.6	????93.1	????91.8	??92.3	??93.3	??90.6
Racemization rate (%)	????98.6	????100	????98.5	????98.0	??97.6	??98.6	??97.8

Computing formula about the racemization rate in this patent is as follows:

Racemization rate=[optical activity of the optical activity/raw material of 1-product] * 100%

The present invention is not limited to the technology described in the embodiment; its description is illustrative; and it is nonrestrictive; authority of the present invention is limited by claim; based on present technique field personnel according to the present invention can change, technology related to the present invention that method such as reorganization obtains, all within protection scope of the present invention.

Claims (7)

1. the catalyst of the racemization method of a α-An Jichun compounds is with Al ₂O ₃Be carrier, active component is the simple substance of Co, Cr, Mo, Rh, Zn, Fe, Cu, Ni, Sr, Ca, Ba or the composite catalyst of multiple simple substance; Or the composite catalyst of simple substance and its oxide, the mass content of each active component is the 5%-20% of catalyst gross mass, the gross activity component content is the 20%-40% of catalyst gross mass.

2. the catalyst of the racemization method of a kind of α-An Jichun compounds as claimed in claim 1 is characterized in that the preferred Mo/Co/Cr of described catalyst activity component, Ni/Co/Zn, Ni/Cu/Zn, Ni/Co/Cr, Co/Cr/Fe ₂O ₃, Co/Sr/Fe ₂O ₃, Co/Ca/Fe ₂O ₃Or Co/Ba/Fe ₂O ₃

3. the racemization method of a α-An Jichun compounds adopts fixed bed, feeds the α-An Jichun compounds of liquid phase or gas phase under atmosphere of hydrogen, and α-An Jichun compounds solvent dilution, solvent load are the 30-90% of reactant liquor gross mass; The charging air speed is 100-20000h ^-1, reaction temperature is 100-300 ℃, reaction pressure 0.5-8Mpa.

4. the racemization method of a kind of α-An Jichun compounds as claimed in claim 3 is characterized in that described reaction temperature preferably at 170-220 ℃, answers pressure preferably at 2.7-4.7MPa.

5. as the racemization method of claim 3 or 4 described a kind of α-An Jichun compounds, it is characterized in that described solvent is oxolane, benzene series solvent, ether solvent, alcohols solvent or water, solvent load is preferably the 45-75% of reactant liquor gross mass.

6. the racemization method of a kind of α-An Jichun compounds as claimed in claim 5 is characterized in that described solvent is oxolane, benzene, toluene, as ether, dioxane, as methyl alcohol, ethanol or water.

7. the racemization method of a kind of alpha-amido alcohols series compound as claimed in claim 3 is characterized in that described alpha-amido alcohols series compound is

R wherein ₁Be C ₁-C ₆The straight chained alkyl or the C of low carbon number ₅-C ₈Low carbon number cycloalkyl or aryl or have substituent aryl; R ₂Be hydrogen or C ₁-C ₆The straight chained alkyl or the C of low carbon number ₅-C ₈Low carbon number cycloalkyl or aryl or have substituent aryl; R ₃Be hydrogen or C ₁-C ₆The straight chained alkyl of low carbon number.