CN104370755A - Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid - Google Patents
Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid Download PDFInfo
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Abstract
The present invention discloses a preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid. The optical activity active 3-amino butanol preparation method comprises: in a solvent, under effects of a hydroboration reduction agent and a Lewis acid, carrying out a reduction reaction on a compound represented by a formlu 65 to produce a compound represented by a formlu 14. The optical activity active 3-amino butyric acid preparation method comprises: carrying out a hydrolysis reaction on a compound represented by a formlu 64 to produce a compound represented by a formlu 65. According to the present invention, the preparation method has characteristics of cheap and easily-available raw materials, simple operation, short process route, no hazard of raw materials, high yield, little waste production, environment protection, high raw material conversion rate, high product chemical purity and high product optical purity, and the industrialization is easily achieved. The formulas 64, 65 and 14 are defined in the instruction.
Description
Technical field
The present invention is specifically related to the preparation method of a kind of optically active 3-amino butanol and 3-aminobutyric acid.
Background technology
Du Lutewei, Dolutegravir, be developed by GlaxoSmithKline PLC company, the medicine of the AntiHIV1 RT activity that FDA ratifies recently, is shown in structural formula 1, and its commodity are called Tivicay.Official FDA represents, HIV crowd needs to treat targetedly according to personal considerations, and have recognised the breakthrough of this medicine of Tivicay, for patient provides new selection.
In a research carrying out for 2011 to 2012 years, after the Tivicay that patient accepts 48 weeks and 96 weeks treats, there is the conditions of patients of 88% to have clear improvement, be better than the Atripla of Gilead company.So in February, 2013, FDA announces the evaluation that will speed up Tivicay, and ratifies with on August 13rd, 2013.Thereafter Canadian healthy department also have approved Du Lutewei on November 4th, 2013.
Tivicay is produced by GlaxoSmithKline PLC, and sold by ViiVHealthcare, both at U.S.'s north card.Tivacay can in order to the extensive one-tenth crowd of HIV through approval, and no matter whether it accepted Tivicay in the past to HIV therapy, or the treatment of other integrase inhibitor; The child that simultaneously also approval can be used in more than 12 years old did not use the treatment of other intergrase in the past; It has wide range of applications.
Because Du Lutewei is very new, domesticly at present also do not see that related development is reported.The summary report that the Du Lutewei route of world patent WO2012018065 to Yuan Yan producer and other developer is correlated with, wherein two typical synthetic routes are A method and B method, as described below.
A method:
B method:
As can be seen from above two kinds of routes, the introducing of chirality functional group is all by key compound 14, and namely (R)-3-amino butanol builds.(R) chiral purity of-3-amino butanol determines the purity of follow-up synthetic intermediate, thus plays a part very important to the highly purified Du Lutewei of synthesis.Therefore exploitation has (R)-3-amino butanol of the route synthesis of high purity of efficient, low cost is reduce Du Lutewei bulk drug cost, promotes the committed step of its range of application.
For having optically active (R)-3-amino butanol and the synthesis of (S)-3-amino butanol, bibliographical information mainly contains Lung biopsy: (one) chemical resolution method; (2) chemical derivatization, (three) enzyme process reduces, and (four) chiral raw material is synthesized, (five) preparative chromatography.Simply described below.
(1) chemical resolution method
In patent US2011/275855, the researchist of BASF AG reports the method that the 3-amino butanol 26 utilizing amygdalic acid 27 to split racemization synthesizes (R)-3-amino butanol.The method is most one of method with practicality in the method for at present report.The same with the disconnecting route of classics, other isomer is got rid of by fractionation by the method, causes wastage of material.General method for splitting is by after target isomer and resolution reagent formation salt (namely 28), more free out with alkali, uses organic solvent extraction.Here because (R)-3-amino butanol has very large water-soluble, so the researchist of BASF does not adopt the conventional free technique extracted again, but using this material 29 of 4-(2-hydroxyethyl) morpholine both as solvent, join in 28 as alkali again, then carry out straight run distillation and obtain target product.Because mixed compound 29 is in the product difficult to removing, so product index is decided to be purity 98% by it, containing have an appointment 1% impurity compound 29.
This method is can one of the route that amplifies of feather weight at present, but due to 29 existence, product purity is restricted.
(2) chemical derivatization
Early stage researchist is introduced by the induction of chiral reagent for the chiral centre in (R)-3-amino butanol.1977, Wojciech J.Stec, at J.Org.Chem.1977, reports and utilize the addition of chirality phenylethylamine and ethyl crotonate to carry out synthesizing chiral compound 32, but yield also only had 33% in 42 (9), 1650-1652.Utilize lithium aluminium hydride reduction to obtain the amino alcohol 33 protected subsequently, then obtain target product through palladium hydrocarbonize.This route yield is low, and uses the lithium aluminum hydride being difficult to industrial operation, produces so be not suitable for amplifying.
Subsequently, the people such as Volkmar Wehner in 2003, in US Patent No. 2003/73723, have done 2 improvement to above-mentioned route.One is that chirality phenylethylamine to be changed into the larger derivative of steric hindrance 34, two be ethyl crotonate is changed into the larger β-crotonic acid tert-butyl ester 35 of steric hindrance.Object wants that when making synthetic compound 36, chiral selectivity increases by increasing steric hindrance.In order to increase selectivity, reaction is carried out at-78 DEG C simultaneously, and utilize expensive inflammable butyllithium.In the reduction of an in the end step, utilize lithium aluminium hydride and trichlorine rate to make reductive agent, and inflammable ether is as solvent, these are all unfavorable for amplifying produces.
Because above-mentioned final step is Lithium aluminum hydride reduction, product is difficult to purify, and the order of its last two steps be have exchanged so the people such as RonaldAlbers utilize during above-mentioned route at 2006 (WO2006/76595).Because the hydro-reduction of palladium hydroxide is placed on finally, be easy to obtain high-purity product.But the yield of the patent report the first step is only 37%.
In order to overcome the shortcoming of the route final step that the people such as Volkmar Wehner in 2003 report in US Patent No. 2003/73723, the people such as the scientist Wataru Kuriyama of STOL company of Japan investigated novel ester group hydro-reduction catalyzer 40, and be successively reported in Advanced Synthesis andCatalysis, 2010, Vol352 (1), 92-96 and US Patent No. 2010/63294.
Simultaneously in order to easy reduction, have selected the less methyl esters being easy to reduce.But the yield of its first step is also only 33%.What is more important, this catalyzer will synthesize through multistep, expensive, and the consumption of its in the end step will reach the mol ratio of 0.2 ~ 0.5%.This also has a lot of work to do from practical application.
The researchist of Japan's STOL also reports the hydro-reduction of the amino acid ester 44 that its new catalyst 40 is protected for Boc simultaneously.Same problem is that catalyst levels is comparatively large, adds that catalyzer itself is difficult to synthesis, is difficult to realize suitability for industrialized production.
In early stage report, also there is other utilization chipal compounds to induce and introduce chiral centre, if Celia Andres etc. was at the Tetrahedron Letter of 1992,1992, Vol.33 (20), 2895-2898 reports the reaction of compound 45 and acetaldehyde, and regrettably its selectivity is poor, the ratio of product 46 two isomer is only 80:20, does not reach the object of selectivity synthesis.
(3) enzyme process reduction
The people such as Paseale Besse in 1999 are at Tetrahedron Assymetry, and 1999, Vol 10 (11), 2213-2224 report a new synthetic route.This route is with cheap methyl aceto acetate 49 for raw material, but the reaction that relates to of whole piece route is complicated, tediously long, makes holistic cost higher, is also unfavorable for suitability for industrialized production.As second step uses Lithium aluminum hydride reduction; 4th step is Mitsunobu reaction, uses more expensive DEAD, and product is because a large amount of triphenylphosphine oxides (deriving from Mitsunobu reagent triphenylphosphine) is difficult to purifying simultaneously; 5th step uses the hydrazine hydrate etc. that toxicity is larger.These shortcomings all result in this route and fail so far to realize industrialization.
(4) chiral raw material synthesis
In order to develop people such as new synthetic route Michal Achmatowicz 2005 at Tetrahedron, 2005,61 (38), 9031-9041 to report with D-alanine be the synthetic route of starting raw material.Although this route raw material D-alanine 55 is easy to get, some reagent used limit the prospect of its widespread use.Such as second step reaction uses dangerously explosive diazomethane as reagent, and only this point just makes this route be difficult to promote, and the reagent that diazomethane does not here have other alternative.A rear step also uses more expensive silver benzoate, and these all limit its range of application.
(5) preparative chromatography
The method that it is raw material that the people such as the Bodil Van Niel of nearest Roche Holding Ag report with the 3-aminobutyric acid of racemization in world patent WO2014/9447.First 3-aminobutyric acid and Cbz-Cl are obtained by reacting the amino acid derivative 61 of protection, obtain one group of raceme (S)-61 and (R)-61 after it through borane reduction.This group raceme is separated by chirality preparative high performance liquid chromatography again, and then palladium carbon catalytic hydrogenation obtains target product.This route utilizes preparative chromatography to carry out, and is only applicable to laboratory scale Fast back-projection algorithm, is difficult to realize suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is preparation method's expensive starting materials in order to overcome optically active 3-amino butanol of the prior art, raw material is inflammable and explosive, material toxicity is large, cost is too high, purity is lower, yield is lower, produce that waste material is more easily to be caused wastage of material and be unfavorable for the defects such as suitability for industrialized production, and provides the preparation method of a kind of optically active 3-amino butanol and 3-aminobutyric acid.Preparation method's cheaper starting materials of the present invention is easy to get, simple to operate, operational path is short, raw material without dangerous, yield is high, produce waste material few, be beneficial to that protection of the environment, feed stock conversion are high, product chemistry purity and optical purity high, and be easy to realize industrialization.
The invention provides a kind of preparation method of compound as shown in Equation 14, it comprises the steps: in solvent, under Borohydride reducing agent and lewis acidic effect, carries out reduction reaction by such as formula the compound shown in 65, generates compound as shown in Equation 14;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; And the configuration of this chiral carbon does not change in described reduction reaction.
Wherein, the Borohydride reducing agent in described reduction reaction can be the Borohydride reducing agent of various routine in this type of reaction of this area, one or more in preferred sodium borohydride, POTASSIUM BOROHYDRIDE and lithium borohydride.
Lewis acid in described reduction reaction can be the Lewis acid of various routine in this type of reaction of this area, one or more in preferred Zinc Chloride Anhydrous, Calcium Chloride Powder Anhydrous and Magnesium Chloride Anhydrous.
The solvent of described reduction reaction can be all kinds of SOLVENTS, preferred anhydrous tetrahydro furan and/or anhydrous methyl tertbutyl ether conventional in this type of reaction of this area.
The volume of the solvent of described reduction reaction and the described mass ratio such as formula the compound shown in 65 preferred (8 ~ 14): 1, more preferably (10 ~ 12): 1, the unit of the volume of the solvent of described reduction reaction is milliliter, and the unit of the described quality such as formula the compound shown in 65 is gram.
Borohydride reducing agent described in described reduction reaction and the described mol ratio such as formula the compound shown in 65 preferred (1.2 ~ 2.2): 1, more preferably (1.3 ~ 2.2): 1, most preferably (1.8 ~ 2.2): 1.
Lewis acid described in described reduction reaction and the described mol ratio such as formula the compound shown in 65 preferred (0.6 ~ 1.05): 1, more preferably (0.95 ~ 1.05): 1.
Described reduction reaction preferably comprises following steps: first described solvent, described Borohydride reducing agent and described Lewis acid are mixed, and stir 20 ~ 50 minutes at 10 ~ 35 DEG C, then be warming up to 50 ~ 60 DEG C to stir 3 ~ 5 hours, then 10 ~ 35 DEG C are cooled to, add described such as formula the compound shown in 65, and control temperature is at 10 ~ 40 DEG C, adds and be slowly warming up to back flow reaction afterwards.
The process of described reduction reaction can adopt the traditional test methods in this area (as TLC or HPLC) to monitor, as reaction end time generally to disappear such as formula the compound shown in 65, the time of described reduction reaction is preferably 24 ~ 30 hours.
After described reduction reaction terminates, preferably, the operation of aftertreatment can also be comprised further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, be preferably: after reaction terminates, reaction system is cooled to 10 ~ 15 DEG C, the slow dropping methyl alcohol (methyl alcohol of 0.4 ~ 0.6 times that preferred volume is the quality such as formula the compound shown in 65, methyl alcohol volume unit is milliliter, unit such as formula the quality of the compound shown in 65 is gram) and aqueous sodium hydroxide solution (being preferably massfraction is the aqueous sodium hydroxide solution of 35 ~ 50%) control temperature at 10 ~ 40 DEG C, stir 3 ~ 5 hours at 10 ~ 35 DEG C after adding, filter, washing (preferably washing with tetrahydrofuran (THF)), filtrate concentrates, underpressure distillation, .
Preferably, the preparation method of described compound as shown in Equation 14, it also comprises the steps: the reaction that is hydrolyzed such as formula the compound shown in 64 further, described in generation such as formula the compound shown in 65;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; And the configuration of chiral carbon does not change in described hydrolysis reaction; Described R is C
1~ C
3alkyl.
Wherein, described C
1~ C
3alkyl preferable methyl or ethyl.
Described hydrolysis reaction preferably carries out under acidic conditions or alkaline condition, more preferably carries out in acid condition.
Described acidic conditions preferably carries out in aqueous hydrochloric acid.
When described hydrolysis reaction carries out in aqueous hydrochloric acid, hydrogenchloride and the preferred 4:1 ~ 8:1 of mol ratio such as formula the compound shown in 64, more preferably 5:1 ~ 6:1 in described aqueous hydrochloric acid.
The temperature of described hydrolysis reaction preferably 90 ~ 100 DEG C, more preferably 95 ~ 100 DEG C.
The process of described hydrolysis reaction can adopt the traditional test methods in this area (as TLC or HPLC) to monitor, as reaction end time generally to disappear such as formula the compound shown in 64, the time of described hydrolysis reaction is preferably 10 ~ 12 hours.
After described hydrolysis reaction terminates, preferably, the operation of aftertreatment can also be comprised further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, be preferably: after reaction terminates, reaction system is carried out concentrate (preferred concentrating under reduced pressure), acetone (the acetone of 1.8 ~ 2.5 times that preferred volume is the quality such as formula the compound shown in 64 is added after being cooled to 30 ~ 40 DEG C, the volume unit of acetone is milliliter, unit such as formula the quality of the compound shown in 64 is gram) making beating, filter, filter cake acetone drip washing, dry, dry gained solid mixes in organic solvent (preferred tetrahydrofuran (THF)) neutralization bases maintaining the temperature under the condition of 10 ~ 50 DEG C, after being cooled to room temperature, filter, washing (preferably washing with tetrahydrofuran (THF)), dry (preferred forced air drying, more preferably the forced air drying under the condition of 60 DEG C), .
The preferred mineral alkali of alkali in " mixing with alkali " in the operation of described aftertreatment and/or organic bases.One or more in the preferred sodium hydroxide of described mineral alkali, potassium hydroxide, lithium hydroxide, sodium methylate, sodium ethylate, potassium tert.-butoxide and sodium tert-butoxide.The preferred triethylamine of described organic bases and/or pyridine.Alkali in " mixing with alkali " in the operation of described aftertreatment and the described mol ratio such as formula the compound shown in 64 preferred (0.7 ~ 1.2): 1, more preferably 1:1.When alkali in " mixing with alkali " in the operation of described aftertreatment is sodium hydroxide, described sodium hydroxide preferably adds with the form of aqueous sodium hydroxide solution, and to be more preferably with massfraction be the aqueous sodium hydroxide solution of 50%, and form adds.
Preferably, the preparation method of described compound as shown in Equation 14, it also comprises the steps: in solvent further, by such as formula the compound shown in 63 under the effect of asymmetric hydrogenation catalyzer, carry out hydrogenation with hydrogen, described in generation such as formula the compound shown in 64;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; Described R is C
1~ C
3alkyl.
Wherein, described C
1~ C
3alkyl preferable methyl or ethyl.
Described asymmetric hydrogenation catalyzer can be the conventional various asymmetric hydrogenation catalyzer of this type of reaction of this area, the asymmetric hydrogenation catalyzer of the title complex class that preferred rhodium and phosphine are formed.When the compound 64 generated is R configuration, asymmetric hydrogenation catalyzer preferred Rh (RcSp-DuanPhos) (COD) BF of the title complex class that described rhodium and phosphine are formed
4, Rh (RcSp-DuanPhos) (NBD) BF
4with one or more in Rh (SSRR-TangPhos) (COD) BF4; When the compound 64 generated is S configuration, asymmetric hydrogenation catalyzer preferred Rh (ScRp-DuanPhos) (COD) BF of the title complex class that described rhodium and phosphine are formed
4and/or Rh (ScRp-DuanPhos) (NBD) BF
4.
The solvent of described hydrogenation can be this area, and this type of reacts the solvent of various routine, preferred alcohols kind solvent.Described alcoholic solvent particular methanol and/or ethanol.
The pressure of hydrogen preferably 1 ~ 10 normal atmosphere in described hydrogenation, more preferably 1 ~ 5 normal atmosphere, most preferably 1 ~ 3 normal atmosphere.
Described hydrogenation preferably carries out at 10 ~ 35 DEG C, more preferably carries out at 20 ~ 30 DEG C.
The consumption of described asymmetric hydrogenation catalyzer can be the various conventional amount used of this type of reacting middle catalyst of this area, preferably, described asymmetric hydrogenation catalyzer and the preferred 1:5000 ~ 1:20000 of the described mol ratio such as formula the compound shown in 63, more preferably 1:8000 ~ 1:10000.
The solvent of described hydrogenation is with the described volume mass such as formula the compound shown in 63 than preferred 4:1 ~ 6:1, and more preferably 4.5:1 ~ 5:1 wherein, and the volume unit of solvent is L, and the mass unit such as formula the compound shown in 63 is kilogram.
The process of described hydrogenation can adopt the traditional test methods in this area (as GC, TLC or HPLC) to monitor, as reaction end time generally to disappear such as formula the compound shown in 63, the time of described hydrogenation is preferably 20 ~ 24 hours.
After described hydrogenation terminates, preferably, the operation of aftertreatment can also be comprised further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, are preferably: after reaction terminates, reaction system concentrated.
Preferably, the preparation method of described compound as shown in Equation 14, also comprises following steps: in a solvent further, under condensation catalyst effect, carry out condensation reaction by such as formula the compound shown in 62 and ethanamide, described in generation such as formula the compound shown in 63;
Wherein, described R is C
1~ C
3alkyl.
Wherein, described C
1~ C
3alkyl preferable methyl or ethyl.
Condensation catalyst in described condensation reaction can be the conventional various catalyzer of this type of reaction of this area, one or more in preferred p-methyl benzenesulfonic acid, boron trifluoride diethyl etherate and polyphosphoric acid.
The solvent of described condensation reaction can be the conventional all kinds of SOLVENTS of this type of reaction of this area, one or more in preferred hexanaphthene, toluene, normal heptane and benzene.
Described ethanamide and the preferred 1.4:1 ~ 3.5:1 of the described mol ratio such as formula the compound shown in 62, more preferably 1.4:1 ~ 1.5:1.
The volume of the solvent of described condensation reaction and the preferred 4:1 ~ 6:1 of mass ratio such as formula the compound shown in 62, wherein the unit of the volume of solvent is for rising, and the unit such as formula the quality of the compound shown in 62 is kilogram.
When described condensation catalyst is p-methyl benzenesulfonic acid, described p-methyl benzenesulfonic acid and the preferred 1:20 ~ 3:20 of the described mass ratio such as formula the compound shown in 62, more preferably 1:20 ~ 7:100.
When described condensation catalyst is boron trifluoride diethyl etherate, in described boron trifluoride diethyl etherate, the content of boron trifluoride can be the various conventional contents of this area condensation reaction boron trifluoride diethyl etherate used.
When described condensation catalyst is boron trifluoride diethyl etherate, described boron trifluoride diethyl etherate and the preferred 1:25 ~ 1:15 of the described mass ratio such as formula the compound shown in 62, more preferably 1:20.
When described condensation catalyst is polyphosphoric acid, the polymerization degree of described polyphosphoric acid can be the various polymerization degree of the routine of the polyphosphoric acid used in the condensation reaction of this area.
When described condensation catalyst is polyphosphoric acid, described polyphosphoric acid and the preferred 1:2 ~ 1:4 of the described mass ratio such as formula the compound shown in 62.
The process of described condensation reaction can adopt the traditional test methods in this area (as GC or TLC) to monitor, as reaction end time generally to reach 9:1 such as formula the compound shown in 63 and the mol ratio such as formula the compound shown in 62, the time of described condensation reaction is preferably more than 24 hours.
After described condensation reaction terminates, preferably, the operation of aftertreatment can also be comprised further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, are preferably: after reaction terminates, reaction system is carried out stratification, after upper strata is cooled to room temperature, add water stratification, get upper organic layer and concentrate, filter, to filter cake vacuum-drying.The described quality adding the water in water stratification and the preferred 1:1.04 ~ 1.5:1 of mass ratio such as formula the compound shown in 62.
Present invention also offers a kind of preparation method such as formula the compound shown in 65, it comprises the steps:, by the reaction that is hydrolyzed such as formula the compound shown in 64, to generate such as formula the compound shown in 65;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; And the configuration of chiral carbon does not change in described hydrolysis reaction; Described R is C
1~ C
3alkyl.
Wherein, the condition of the method for described hydrolysis reaction ditto described in.
In the present invention, described razaxaban related substance as shown in Equation 14, preferably, its synthetic route is as follows:
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; And the configuration of chiral carbon does not change in described hydrolysis reaction; Described R is C
1~ C
3alkyl.
On the basis meeting this area general knowledge, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: optically active 3-amino butanol of the present invention preparation method's cheaper starting materials is easy to get, simple to operate, operational path is short, raw material without dangerous, yield is high, produce waste material few, be beneficial to that protection of the environment, feed stock conversion are high, product chemistry purity and optical purity high, and be easy to realize industrialization.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Wherein used catalyst [Rh ((Rc, Sp)-Duanpos) (COD)] BF4, [Rh ((Sc, Rp)-Duanpos) (COD)] BF4 and Rh (SSRR-TangPhos) (COD) BF4 can buy from STREM or ALDRICH company.
The synthesis (Catalyzed by P-Toluenesulfonic Acid) of embodiment 1:3-kharophen ethyl crotonate
In 500 liters of reactors, add 52 kilograms of methyl aceto acetates, 35 kilograms of ethanamides and 300L hexanaphthene, fully stir.Then add 3 kilograms of p-methyl benzenesulfonic acids, and be slowly warming up to and reflux and pass through fraction water device water-dividing.When reaction about 24 hours, sampling GC detected, and when product and raw material ratio reach 9:1, stopped stirring, left standstill.Layering while hot, upper strata is cooled to room temperature, then adds 50 kilograms, water washing layering, and upper organic layer is concentrated until a large amount of solid is separated out, and filter and obtain white crystal, vacuum-drying obtains white solid 37.6 kilograms, yield 55%.Fusing point: 64-65 DEG C.Vapor detection purity: 98.7%.
1H NMR(300MHz,CDCl3)：δ1.28(t,J＝7.2Hz,3H),2.14(s,3H),2.38(s,3H),4.15(q,J＝7.2Hz,2H),4.89(s,1H),11.15(bs,1H)。
The synthesis (boron trifluoride diethyl etherate catalysis) of embodiment 2:3-kharophen ethyl crotonate
In 5 liters of round-bottomed flasks, add 500 grams of methyl aceto acetates, 340 grams of ethanamides and 3 liters of hexanaphthenes, fully stir.Then add 25 grams of boron trifluoride diethyl etherate, and be slowly warming up to and reflux and pass through fraction water device water-dividing.When reaction about 24 hours, sampling GC detected, and when product and raw material ratio reach 9:1, stopped stirring, left standstill.Layering while hot, upper strata is cooled to room temperature, then adds 500 milliliters, water washing layering, and upper organic layer is concentrated until a large amount of solid is separated out, and filter and obtain white crystal, vacuum-drying obtains white solid 394 grams, yield 61%.Fusing point: 64.5-65 DEG C.Vapor detection purity: 99.1%.
1H NMR(300MHz,CDCl
3)：δ1.28(t,J＝7.2Hz,3H),2.14(s,3H),2.38(s,3H),4.15(q,J＝7.2Hz,2H),4.89(s,1H),11.15(bs,1H)。
Embodiment 3:(R) synthesis of-3-acetylminobutyric acid ethyl ester
200 grams of 3-kharophen ethyl crotonates and 800 ml methanol are added in 2L hydrogenation reaction cauldron, nitrogen replacement 30 minutes; Then under nitrogen protection by 83 milligrams of Rh (SSRR-TangPhos) (COD) BF
4add in reactor.Carefully add hydrogen, under room temperature, maintain 1 ~ 5 normal atmosphere reaction 20 ~ 24 hours; Gas chromatographic detection raw material reaction is complete, and discharging concentrates to obtain oily matter 186 grams, yield 92%, ee99.4%.Ee vapor detection condition: Astec CHIRALDEXTM B-DM 30mx0.32mmx0.12um chromatographic column.Carrier gas: nitrogen; Flow velocity: 1.5mL/min; Column temperature: 110 DEG C of constant temperature; Retention time: R ?3 ?acetylminobutyric acid ethyl ester 14.7 minutes, S-3 ?acetylminobutyric acid ethyl ester, 12.8 minutes.
1H NMR(300MHz,CDCl
3):δ6.15(brs,1H),4.39-4.31(m,1H),4.21(q,7.2Hz,2H),2.52(dd,2.8,5.3Hz,2H),1.96(s,3H),1.27(t,J＝7.2Hz,3H),1.23(d,J＝6.6Hz,3H)。
Embodiment 4:(R) synthesis of-3-acetylminobutyric acid ethyl ester
100 kilograms of 3-kharophen ethyl crotonates and 500 liters of methyl alcohol are added in 1000L hydrogenation reaction cauldron, nitrogen replacement 60 minutes; Then under nitrogen protection by 45 grams of Rh (RcSp-DuanPhos) (COD) BF
4add in reactor.Carefully add hydrogen, under room temperature, maintain 1-5 normal atmosphere reaction 20 ~ 24 hours; Gas chromatographic detection raw material reaction is complete, and discharging concentrates to obtain oily matter 88 kilograms, yield 87%, ee99.2%.Ee vapor detection condition: Astec CHIRALDEXTM B-DM30mx0.32mmx0.12um chromatographic column.Carrier gas: nitrogen; Flow velocity: 1.5mL/min; Column temperature: 110 DEG C of constant temperature; Retention time: R ?3 ?acetylminobutyric acid ethyl ester 14.7 minutes, S-3 ?acetylminobutyric acid ethyl ester, 12.8 minutes.
1H NMR(300MHz,CDCl
3):δ6.15(brs,1H),4.39-4.31(m,1H),4.21(q,7.2Hz,2H),2.52(dd,2.8,5.3Hz,2H),1.96(s,3H),1.27(t,J＝7.2Hz,3H),1.23(d,J＝6.6Hz,3H)。
Embodiment 5:(S) synthesis of-3-acetylminobutyric acid ethyl ester
250 grams of 3-kharophen ethyl crotonates and 1 liter of methyl alcohol are joined in 2L hydrogenation reaction cauldron, nitrogen replacement 30 minutes; Then under nitrogen protection by 135 milligrams of Rh (ScRp-DuanPhos) (COD) BF
4add in reactor.Carefully add hydrogen, under room temperature, maintain 1 ~ 5 normal atmosphere reaction 20 ~ 24 hours; Gas chromatographic detection raw material reaction is complete, and discharging concentrates to obtain oily matter 232 grams, yield 91%, ee99.2%.Ee vapor detection condition: Astec CHIRALDEXTM B-DM 30mx0.32mmx0.12um chromatographic column.Carrier gas: nitrogen; Flow velocity: 1.5mL/min; Column temperature: 110 DEG C of constant temperature; Retention time: R ?3 ?acetylminobutyric acid ethyl ester 14.7 minutes, S-3 ?acetylminobutyric acid ethyl ester, 12.8 minutes.
1H NMR(300MHz,CDCl
3):δ6.15(brs,1H),4.39-4.31(m,1H),4.21(q,7.2Hz,2H),2.52(dd,2.8,5.3Hz,2H),1.96(s,3H),1.27(t,J＝7.2Hz,3H),1.23(d,J＝6.6Hz,3H)。
Embodiment 6:(R) synthesis of-3-amino butanol
(R)-3-acetylminobutyric acid ethyl ester 1750 grams and 3650 grams water that embodiment 4 obtains are added in 20L tetra-mouthfuls of reaction flasks that mechanical stirring, reflux condensing tube, thermometer are housed, the 5500 grams of concentrated hydrochloric acids massfraction 36% of hydrogenchloride (in the concentrated hydrochloric acid), are heated to 95 ~ 100 DEG C and keep 12 hours.Water is steamed in decompression, closely dry to reaction solution, adds the making beating of 3.4L acetone after being cooled to 30 ~ 40 DEG C; Separate out solid, filter, acetone drip washing, dry must about 1200 grams of white solids.This white solid and 1.5 liters of anhydrous tetrahydro furans are added in the round-bottomed flask of 10 liters and stir, the aqueous sodium hydroxide solution of the lower dropping 660 gram 50% of cooling control temperature are at 10 ~ 50 DEG C.Dropwise and obtain oyster white soup compound, be cooled to room temperature, filter, a small amount of THF of solid washs, and gained solid forced air drying (60 DEG C) obtains about 1280 grams of white solids.
In the reactor of 50L, add 13L anhydrous tetrahydro furan and 1067 grams of Zinc Chloride Anhydrouss (having a little heat release), careful batch adds 590 grams of sodium borohydrides (noting heat release and aerogenesis).Stirring at room temperature 30 minutes, is then warming up to 50 ~ 60 DEG C and stirs 3 hours.After cool to room temperature, add gained 1280 grams of white solids above, and control temperature is at 10 ~ 40 DEG C in batches.After adding, be slowly warming up to back flow reaction 24 hours.System grizzle is suspended system, is cooled to 10-15 DEG C, slowly drip 640 ml methanol and 200 gram of 40% aqueous sodium hydroxide solution, and control temperature is at 10 ~ 40 DEG C.After adding, stirring at room temperature 3 ~ 5 hours.Filter, THF washs, and is filtered dry to obtain colourless liquid; Concentrated, underpressure distillation (10 ~ 65 DEG C) obtains clear viscous liquids R-3-amino butanol 495 grams, yield 54%.Purity 99.2%, ee99.3%.
Purity gas-chromatography directly measures.Ee measures: first reacted with Carbobenzoxy Chloride in aqueous sodium hydroxide solution by 3-amino butanol and generate N-Cbc-3-amino butanol, then use Liquid Detection.Chromatographic column AD-H; Mobility normal hexane: Virahol (9:1); Flow velocity, 1 ml/min.Determined wavelength, 210 nanometers.Retention time, S-isomer, 11.1 minutes, R-isomer 12.2 minutes.
1HNMR(300MHz,DMSO,ppm):δ4.48(3H,s),3.47(2H,s),2.96(1H,s),1.47-1.41(2H,q),1.02-0.99(3H,d)。
Embodiment 7:(S) synthesis of-3-amino butanol
70 grams of S-3-acetylminobutyric acid ethyl esters are added in 1L tetra-mouthfuls of reaction flasks that mechanical stirring, reflux condensing tube, thermometer are housed, 150 grams of water, the 220 grams of concentrated hydrochloric acids massfraction 36% of hydrogenchloride (in the concentrated hydrochloric acid), are heated to 95 ~ 100 DEG C and keep 10 hours.Water is steamed in decompression, closely dry to reaction solution, adds 150 milliliters of acetone making beating after being cooled to 30-40 DEG C; Separate out solid, filter, acetone drip washing, dry must about 45 grams of white solids.This white solid and 100 milliliters of anhydrous tetrahydro furans are added in the round-bottomed flask of 2 liters and stir, add 17 grams of solid sodium methylates under cooling and control temperature at 10 ~ 50 DEG C.Dropwise and obtain oyster white soup compound, be cooled to room temperature, filter, a small amount of THF of solid washs, and gained solid forced air drying (60 DEG C) obtains about 49 grams of white solids.
In the reactor of 2L, add 600 milliliters of anhydrous tetrahydro furans and 43 grams of Zinc Chloride Anhydrouss (having a little heat release), careful batch adds 24 grams of sodium borohydrides (noting heat release and aerogenesis).Stirring at room temperature 30 minutes, is then warming up to 50-60 DEG C and stirs 3 hours.After cool to room temperature, add gained 49 grams of white solids above, and control temperature is at 10 ~ 40 DEG C in batches.After adding, be slowly warming up to back flow reaction 24 hours.System grizzle is suspended system, is cooled to 10-15 DEG C, slowly drip 25 ml methanol and 8 gram of 40% aqueous sodium hydroxide solution, and control temperature is at 10 ~ 40 DEG C.After adding, stirring at room temperature 3-5 hour.Filter, THF washs, and is filtered dry to obtain colourless liquid; Concentrated, underpressure distillation (10 ~ 65 DEG C) obtains clear viscous liquids R-3-amino butanol 17 grams, yield 47%.Purity 99.1%, ee99.2%.
Purity gas-chromatography directly measures.Ee measures: first reacted with Carbobenzoxy Chloride in aqueous sodium hydroxide solution by 3-amino butanol and generate N-Cbc-3-amino butanol, then use Liquid Detection.Chromatographic column AD-H; Mobility normal hexane: Virahol (9:1); Flow velocity, 1 ml/min.Determined wavelength, 210 nanometers.Retention time, S-isomer, 11.1 minutes, R-isomer 12.2 minutes.
1HNMR(300MHz,DMSO,ppm):δ4.48(3H,s),3.47(2H,s),2.96(1H,s),1.47-1.41(2H,q),1.02-0.99(3H,d)。
Claims (12)
1. a preparation method for compound as shown in Equation 14, it is characterized in that, it comprises the steps: in solvent, under Borohydride reducing agent and lewis acidic effect, carries out reduction reaction by such as formula the compound shown in 65, generates compound as shown in Equation 14;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; And the configuration of this chiral carbon does not change in described reduction reaction.
2. preparation method as claimed in claim 1, is characterized in that, the Borohydride reducing agent in described reduction reaction is one or more in sodium borohydride, POTASSIUM BOROHYDRIDE and lithium borohydride;
And/or the Lewis acid in described reduction reaction is one or more in Zinc Chloride Anhydrous, Calcium Chloride Powder Anhydrous and Magnesium Chloride Anhydrous;
And/or the solvent of described reduction reaction is anhydrous tetrahydro furan and/or anhydrous methyl tertbutyl ether;
And/or, the volume of the solvent of described reduction reaction and the described mass ratio such as formula the compound shown in 65 are (8 ~ 14): 1, the unit of the volume of the solvent of described reduction reaction is milliliter, and the unit of the described quality such as formula the compound shown in 65 is gram;
And/or the Borohydride reducing agent described in described reduction reaction and the described mol ratio such as formula the compound shown in 65 are (1.2 ~ 2.2): 1;
And/or the Lewis acid described in described reduction reaction and the described mol ratio such as formula the compound shown in 65 are (0.6 ~ 1.05): 1.
3. preparation method as claimed in claim 1 or 2, it is characterized in that, described reduction reaction comprises following steps: first described solvent, described Borohydride reducing agent and described Lewis acid are mixed, and stir 20 ~ 50 minutes at 10 ~ 35 DEG C, be then warming up to 50 ~ 60 DEG C and stir 3 ~ 5 hours, be then cooled to 10 ~ 35 DEG C, add described such as formula the compound shown in 65, and control temperature is at 10 ~ 40 DEG C, adds and be slowly warming up to back flow reaction afterwards;
And/or the volume of the solvent of described reduction reaction and the described mass ratio such as formula the compound shown in 65 are (10 ~ 12): 1; The unit of the volume of the solvent of described reduction reaction is milliliter, and the unit of the described quality such as formula the compound shown in 65 is gram;
And/or the Borohydride reducing agent described in described reduction reaction and the described mol ratio such as formula the compound shown in 65 are (1.3 ~ 2.2): 1;
And/or the Lewis acid described in described reduction reaction and the described mol ratio such as formula the compound shown in 65 are (0.95 ~ 1.05): 1;
And/or, after described reduction reaction terminates, also comprise the operation of aftertreatment further; The method of described aftertreatment and condition are: after reaction terminates, reaction system is cooled to 10 ~ 15 DEG C, slowly drip methyl alcohol and aqueous sodium hydroxide solution and control temperature at 10 ~ 40 DEG C, stir 3 ~ 5 hours at 10 ~ 35 DEG C after adding, filter, washing, filtrate concentrates, underpressure distillation.
4. preparation method as claimed in claim 1, it is characterized in that, the preparation method of described compound as shown in Equation 14, it also comprises the steps: the reaction that is hydrolyzed such as formula the compound shown in 64 further, described in generation such as formula the compound shown in 65;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; And the configuration of chiral carbon does not change in described hydrolysis reaction; Described R is C
1~ C
3alkyl.
5. preparation method as claimed in claim 4, is characterized in that, described C
1~ C
3alkyl is methyl or ethyl;
And/or described hydrolysis reaction carries out under acidic conditions or alkaline condition;
And/or the temperature of described hydrolysis reaction is 90 ~ 100 DEG C;
And/or, after described hydrolysis reaction terminates, also comprise the operation of aftertreatment further; The method of described aftertreatment and condition are: after reaction terminates, reaction system is concentrated, adds acetone making beating after being cooled to 30 ~ 40 DEG C, filter, filter cake acetone drip washing, drying, dry gained solid mixes with alkali, after being cooled to room temperature in organic solvent maintaining the temperature under the condition of 10 ~ 50 DEG C, filter, washing, dry.
6. preparation method as claimed in claim 5, it is characterized in that, described hydrolysis reaction carries out in acid condition;
And/or the temperature of described hydrolysis reaction is 95 ~ 100 DEG C;
And/or, after described hydrolysis reaction terminates, when also comprising the operation of aftertreatment further, in described post-processing operation, described simmer down to concentrating under reduced pressure; And/or, the acetone of 1.8 ~ 2.5 times that the volume of described acetone is the quality such as formula the compound shown in 64, the volume unit of acetone is milliliter, and the unit such as formula the quality of the compound shown in 64 is gram; And/or the organic solvent in " dry gained solid is maintaining the temperature under the condition of 10 ~ 50 DEG C at organic solvent " in the operation of described aftertreatment is tetrahydrofuran (THF); And/or the alkali in " mixing with alkali " in the operation of described aftertreatment is mineral alkali and/or organic bases; And/or the alkali in " mixing with alkali " in the operation of described aftertreatment and the described mol ratio such as formula the compound shown in 64 are (0.7 ~ 1.2): 1.
7. preparation method as claimed in claim 6, it is characterized in that, described acidic conditions carries out in aqueous hydrochloric acid; When described hydrolysis reaction carries out in aqueous hydrochloric acid, in described aqueous hydrochloric acid, hydrogenchloride and the mol ratio such as formula the compound shown in 64 are 4:1 ~ 8:1.
8. preparation method as claimed in claim 4, it is characterized in that, the preparation method of described compound as shown in Equation 14, it also comprises the steps: in solvent further, by such as formula the compound shown in 63 under the effect of asymmetric hydrogenation catalyzer, carry out hydrogenation with hydrogen, described in generation such as formula the compound shown in 64;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; Described R is C
1~ C
3alkyl.
9. preparation method as claimed in claim 8, is characterized in that, wherein, and described C
1~ C
3alkyl is methyl or ethyl;
And/or described asymmetric hydrogenation catalyzer is the asymmetric hydrogenation catalyzer of the title complex class that rhodium and phosphine are formed; When the compound 64 generated is R configuration, the asymmetric hydrogenation catalyzer of the title complex class that described rhodium and phosphine are formed is Rh (RcSp-DuanPhos) (COD) BF
4, Rh (RcSp-DuanPhos) (NBD) BF
4with one or more in Rh (SSRR-TangPhos) (COD) BF4; When the compound 64 generated is S configuration, the asymmetric hydrogenation catalyzer of the title complex class that described rhodium and phosphine are formed is Rh (ScRp-DuanPhos) (COD) BF
4and/or Rh (ScRp-DuanPhos) (NBD) BF
4;
And/or the solvent of described hydrogenation is alcoholic solvent;
And/or the pressure of hydrogen is 1 ~ 10 normal atmosphere in described hydrogenation;
And/or described hydrogenation carries out at 10 ~ 35 DEG C;
And/or described asymmetric hydrogenation catalyzer and the described mol ratio such as formula the compound shown in 63 are 1:5000 ~ 1:20000;
And/or the solvent of described hydrogenation and the described volume mass such as formula the compound shown in 63 are than being 4:1 ~ 6:1, and the volume unit of solvent is L, the mass unit such as formula the compound shown in 63 is kilogram.
10. preparation method as claimed in claim 8 or 9, it is characterized in that, the preparation method of described compound as shown in Equation 14, also comprise following steps further: in a solvent, under condensation catalyst effect, carry out condensation reaction by such as formula the compound shown in 62 and ethanamide, described in generation such as formula the compound shown in 63;
Wherein, described R is C
1~ C
3alkyl.
11. preparation methods as claimed in claim 10, is characterized in that, described C
1~ C
3alkyl is methyl or ethyl;
And/or the condensation catalyst in described condensation reaction is one or more in p-methyl benzenesulfonic acid, boron trifluoride diethyl etherate and polyphosphoric acid; When described condensation catalyst is p-methyl benzenesulfonic acid, described p-methyl benzenesulfonic acid and the described mass ratio such as formula the compound shown in 62 are 1:20 ~ 3:20; When described condensation catalyst is boron trifluoride diethyl etherate, described boron trifluoride diethyl etherate and the described mass ratio such as formula the compound shown in 62 are 1:25 ~ 1:15; When described condensation catalyst is polyphosphoric acid, described polyphosphoric acid and the described mass ratio such as formula the compound shown in 62 are 1:2 ~ 1:4;
And/or the solvent of described condensation reaction is one or more in hexanaphthene, toluene, normal heptane and benzene;
And/or described ethanamide and the described mol ratio such as formula the compound shown in 62 are 1.4:1 ~ 3.5:1;
And/or the volume of the solvent of described condensation reaction is 4:1 ~ 6:1 with the mass ratio such as formula the compound shown in 62, wherein the unit of the volume of solvent is for rising, and the unit such as formula the quality of the compound shown in 62 is kilogram.
12. 1 kinds of preparation methods such as formula the compound shown in 65, it comprises the steps:, by the reaction that is hydrolyzed such as formula the compound shown in 64, to generate such as formula the compound shown in 65;
Wherein, the carbon of * mark is chiral carbon, and it is S type or R type; And the configuration of chiral carbon does not change in described hydrolysis reaction; Described R is C
1~ C
3alkyl;
Wherein, the condition of the method for described hydrolysis reaction is with according to any one of claim 4 ~ 7.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961640A (en) * | 2015-07-26 | 2015-10-07 | 嵊州市油脂化工有限公司 | Preparation method of optically pure 3-amino-1-butanol |
| CN105001098A (en) * | 2015-07-26 | 2015-10-28 | 嵊州市油脂化工有限公司 | Method for preparing 3(R)/(S)-amidogen-1-butanol |
| CN106966912A (en) * | 2017-04-01 | 2017-07-21 | 沧州那瑞化学科技有限公司 | (R) preparation method of 3 amino butanols |
| CN108374027A (en) * | 2018-03-09 | 2018-08-07 | 长兴制药股份有限公司 | A kind of preparation method of R-3- aminobutyric acids |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1357534A (en) * | 2001-07-20 | 2002-07-10 | 昆山双鹤药业有限责任公司 | Prepn. of L-2-amino propanol |
| CN101027278A (en) * | 2004-07-09 | 2007-08-29 | 沃尼尔－朗伯有限责任公司 | Preparation of beta-amino acids having affinity for the alpha-2-delta protein |
| WO2014009447A1 (en) * | 2012-07-11 | 2014-01-16 | F. Hoffmann-La Roche Ag | ARYL SULTAM DERIVATIVES AS RORc MODULATORS |
| TW201410674A (en) * | 2012-06-15 | 2014-03-16 | 大正製藥股份有限公司 | Heteroaromatic methyl cyclic amine derivatives |
-
2014
- 2014-09-22 CN CN201410488279.2A patent/CN104370755B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1357534A (en) * | 2001-07-20 | 2002-07-10 | 昆山双鹤药业有限责任公司 | Prepn. of L-2-amino propanol |
| CN101027278A (en) * | 2004-07-09 | 2007-08-29 | 沃尼尔－朗伯有限责任公司 | Preparation of beta-amino acids having affinity for the alpha-2-delta protein |
| TW201410674A (en) * | 2012-06-15 | 2014-03-16 | 大正製藥股份有限公司 | Heteroaromatic methyl cyclic amine derivatives |
| WO2014009447A1 (en) * | 2012-07-11 | 2014-01-16 | F. Hoffmann-La Roche Ag | ARYL SULTAM DERIVATIVES AS RORc MODULATORS |
Non-Patent Citations (2)
| Title |
|---|
| SIMON P. B. OVENDEN AND ROBERT J. CAPON: "Amphilactams A-D: Novel Nematocides from Southern Australian Marine Sponges of the Genus Amphimedon", 《J. ORG. CHEM.》 * |
| 张春华等: "一种改进的制备手性氨基醇的方法", 《有机化学》 * |
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