CN101274938A - Preparation for (S) or (R)-2-methyl-CBS-chiral oxazaborolidine and toluene solution thereof - Google Patents
Preparation for (S) or (R)-2-methyl-CBS-chiral oxazaborolidine and toluene solution thereof Download PDFInfo
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- CN101274938A CN101274938A CNA200710038517XA CN200710038517A CN101274938A CN 101274938 A CN101274938 A CN 101274938A CN A200710038517X A CNA200710038517X A CN A200710038517XA CN 200710038517 A CN200710038517 A CN 200710038517A CN 101274938 A CN101274938 A CN 101274938A
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Abstract
The invention discloses an (S) or (R)-2-methyl-CBS-oxazolo borane and a preparation method of the toluene solution thereof, which comprises the following steps: borane tetrahydrofuran solution, carbon monoxide, (S) or (R)-proline, etc., which are relatively cheap substances, serve as raw materials and (S) or (R)-2-methyl-CBS-oxazolo borane or the toluene solution of (S) or (R)-2-methyl-CBS-oxazolo borane is obtained through six steps of reaction. A synthesis process is carried out at a temperature that is easily controlled; a reaction solvent adopted is tetrahydrofuran which can be recycled with water, acid and peroxide removed by calcium oxide. Therefore, the method of the invention is convenient for industrial production, can meet the needs of relevant parties and has relatively vast industrial application prospect.
Description
Technical field
The present invention relates to the preparation method of (S)-2-methyl-CBS-oxazole borine and toluene solution thereof and (R)-2-methyl-CBS-oxazole borine and toluene solution thereof.
Background technology
Chiral drug is the field, forward position of pharmaceutical industries, it is reported, and the world's single mapping form chiral drug sales volume sustainable growth, its market share 1996 was 27%, had been increased to 61% by 2006.
(S)-2-methyl-CBS-oxazole borine and (R)-2-methyl-CBS-oxazole borine, because can the height enantioselectivity, near quantitative, catalysis borane reduction ketone becomes secondary alcohol [Elias J.Coreyand Christopher J.Helal fast, Angew.Chem.Int.Ed., the 37th volume, the 1989th page (1998)], so on medicine is synthetic, be widely used.For example: antiemetic A Rui smooth important intermediate (R)-3,5-di-trifluoromethyl-phenylethyl alcohol is exactly by (S)-2-methyl-CBS-oxazole borine catalysis borane reduction 3, [the people such as Karel M.J.Brands that 5-di-trifluoromethyl-methyl phenyl ketone obtains, J.Am.Chem.Soc., the 125th volume, the 8th phase, the 2131st page (2003)]; Though the Ezetimbe+ Simvastatin of Merck ﹠ Co., Inc. and the cooperative development of Schering Plough company is in just list marketing mid-term in 2004, but show surprising, become the fastest medicine of sales growth, wherein synthesizing of Ezetimbe just has been applied to (R)-2-methyl-CBS-oxazole borine [Elizabeth R.Burkhardt and Karl Matos, Chemical Reviews, the 106th volume, the 7th phase, the 2640th page (2006)]; Complete synthesis (the S)-2-methyl-CBS-oxazole borine of also having used with compound trans-replacement-tetramethyleneimine (1) of huge biology and pharmaceutical active.
With the borine is starting raw material, and synthetic (S)-2-methyl-CBS-oxazole borine and (R)-2-methyl-CBS-oxazole borine and toluene solution thereof also do not have the pertinent literature report.Prior preparation method is:
(S)-1, the 1-diphenylprolinol, (R)-1,1-diphenylprolinol and methyl boron acid anhydrides react in toluene and obtain (S)-2-methyl-CBS-oxazole borine and (R)-2-methyl-CBS-oxazole borine [people such as David J.Mathre, J.Org.Chem., the 56th volume, 751 pages～762 pages, 1991], this preparation method is to (S)-1, the 1-diphenylprolinol, (R)-1, the 1-diphenylprolinol is synthetic to the strict control of temperature of reaction, wherein by (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride, (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride and synthetic (S)-1 of Grignard reagent, 1-diphenylprolinol vitriol, (R)-1,1-diphenylprolinol vitriol one step needs accurate control reaction temperature-10 ℃～-15 ℃, because this step reaction very exothermic, industrial scale operation time-10 ℃～-15 ℃ of difficult controls, the used solvents tetrahydrofurane of this technology need be through very loaded down with trivial details no water treatment, and can not recycle, this raw materials cost that has caused 60% is a solvents tetrahydrofurane, so the process conditions that people such as David J.Mathre provide is difficult to control, cost is higher; (S)-1 in this method simultaneously, 1-diphenylprolinol, (R)-1,1-diphenylprolinol and methyl boron acid anhydrides react a step in toluene need a straight-through nitrogen to guarantee to be reflected under the anhydrous and oxygen-free condition to carry out, and required nitrogen amount is bigger during mass production.
The existing method for preparing the methyl boron acid anhydrides is to feed carbon monoxide in the system of a constant voltage in the borine tetrahydrofuran (THF), require reaction more than 6～8 hours, and there is the part borine not send out and answers [Herbert C.Brown and Thomas E.Cole, Organometallics, the 4th volume, the 5th phase, 820 pages, (1985)].
Therefore, there are many weak points in the preparation method of present preparation (S) or (R)-2-methyl-CBS-oxazole borine and toluene solution solution thereof, can not satisfy the needs in relevant field.
Summary of the invention
The technical issues that need to address of the present invention are the preparation methods that disclose a kind of (S) or (R)-2-methyl-CBS-oxazole borine and toluene solution solution thereof, to overcome the above-mentioned defective that prior art exists.
Method of the present invention comprises the steps:
(1) (S)-proline(Pro) or (R)-proline(Pro) in tetrahydrofuran (THF) with the tetrahydrofuran solution reaction of triphosgene, obtain (S)-proline(Pro)-N-formyl chloride (IV) or (R)-proline(Pro)-N-formyl chloride (V):
(S)-mol ratio of proline(Pro) or (R)-proline(Pro) and triphosgene is 1: 0.35～0.70;
Reaction times is 1～3 hour, and temperature of reaction is 15～40;
(2) (S)-proline(Pro)-N-formyl chloride or (R)-proline(Pro)-N-formyl chloride reacts with triethylamine in tetrahydrofuran (THF), (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride (VI) or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride (VII) is collected in-5～5 ℃ of reactions 0.5～1.0 hour then from reaction product;
(S)-mol ratio of proline(Pro)-N-formyl chloride or (R)-proline(Pro)-N-formyl chloride and triethylamine is 1: 1.0～1.1;
(3) (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride reacts with phenyl grignard reagent in tetrahydrofuran (THF), temperature is-4 ℃～-10 ℃, reacted 2.5～8 hours, continue reaction 0.5～7 hour at 20～30 ℃ then, reaction solution adds in the sulfuric acid, and suction filtration is collected (S)-1,1-diphenylprolinol vitriol (VIII) and (R)-1,1-diphenylprolinol vitriol (IX);
The preferred phenyl-magnesium-chloride of said phenyl grignard reagent, phenyl-magnesium-bromide, the molar weight of its adding are 250～350% of (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride;
Said vitriolic concentration is 1.8～2.2M, and the molar weight that vitriolic adds is 350～450% of (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride;
(4) (S)-1,1-diphenylprolinol vitriol or (R)-1, the tetrahydrofuran (THF) suspension liquid of 1-diphenylprolinol vitriol and aqueous sodium hydroxide solution reaction, adopt toluene from reaction product, to extract collection (S)-1 then, 1-diphenylprolinol (X) toluene, tetrahydrofuran solution and (R)-1,1-diphenylprolinol (XI) toluene, tetrahydrofuran solution, cut below 85 ℃ in the reaction product is removed in air distillation then, comprise water and tetrahydrofuran (THF), obtain (S)-1,1-diphenylprolinol (X) toluene solution and (R)-1,1-diphenylprolinol (XI) toluene solution;
The concentration of said aqueous sodium hydroxide solution is 1.8～2.2M, and the mole dosage of sodium hydroxide is (S)-1,1-diphenylprolinol vitriol or (R)-1,100～300% of 1-diphenylprolinol vitriol;
(5) carbon monoxide and borine tetrahydrofuran solution react under catalyst, and temperature of reaction is 20～45 ℃, and the reaction times is 2～12 hours, and reaction pressure is 1～2atm, and after reaction finished, rectifying obtained methyl boron acid anhydrides (III) from reaction product;
The mole dosage of carbon monoxide is 100～120% of a borine, and the concentration of borine tetrahydrofuran solution is 0.5～2.0M;
Said catalyzer is selected from lithium borohydride, and consumption is 5～10% of a borine mole dosage;
(6) (S)-1 of methyl boron acid anhydrides and step (4) acquisition, the toluene solution of 1-diphenylprolinol or (R)-1, the reaction of 1-diphenylprolinol toluene solution, temperature of reaction is 20～30 ℃, reaction times is 0.5～2 hour, be warming up to 110～130 ℃ then, finally obtain target product: (S)-2-methyl-CBS-oxazole borine (I) or its toluene solution, or (R)-2-methyl-CBS-oxazole borine (II) or its toluene solution;
(S)-1,1-diphenylprolinol or (R)-1,1-diphenylprolinol and methyl boron acid anhydrides and mol ratio be 1: 0.3～1.0;
By technical scheme disclosed in this invention as seen, method of the present invention, by borine tetrahydrofuran solution, carbon monoxide, (S) or (R)-more cheap raw material such as proline(Pro) obtains (S) or (R)-2-methyl-CBS-oxazole borine and toluene solution thereof through six-step process, synthesis technique carries out under temperature more easy to control, the reaction solvent tetrahydrofuran (THF) that is adopted, can dewater by calcium oxide, acid and superoxide, thereby can recycle.This shows that method of the present invention is convenient to suitability for industrialized production, can satisfy the needs of the parties concerned, have bigger industrializing implementation prospect.
Embodiment
Embodiment 1
Under the nitrogen atmosphere, (0.27mol, 1.0eq), anhydrous tetrahydro furan 307ml forms suspension liquid to add (S)-proline 3 0.7g in exsiccant 1L there-necked flask bottle.Water-bath is chilled to 17 ℃.By constant pressure funnel in reaction flask, drip the 155ml triphosgene tetrahydrofuran solution (contain triphosgene 28.5g, 0.096mol, 0.36eq).Drip 17 ℃ of process control temps, the control rate of addition added in 30 minutes.Produce cloud insolubles in the reaction system this moment.Dropwise and be warming up to 30 ℃ of reactions 1 hour.This moment, system was clarified substantially, was directly used in the next step.
Embodiment 2
Reaction solution among the embodiment 1 is controlled 0 ℃ of left and right sides temperature drip the 37ml triethylamine under nitrogen protection, drip off about 20 minutes.0 ℃ was reacted 30 minutes, and removed by filter triethylamine hydrochloride.With 60ml anhydrous tetrahydro furan washing triethylamine hydrochloride, triplicate merges organic phase.The not purified the next step that is directly used in of product.
Embodiment 3
The tetrahydrofuran solution that in 2L exsiccant there-necked flask, adds 400ml (2M) phenyl-magnesium-chloride under the nitrogen atmosphere, subzero about the 5 ℃ tetrahydrofuran solutions that in there-necked flask, drip embodiment 2 products of controlled temperature.2.5 hour add, subzero 5 ℃ are continued reaction 5.5 hours, 20 ℃ of reactions 7 hours.Controlled temperature is added to anti-drop in 533ml (1M) sulfuric acid about 5 ℃, adds in about 50 minutes.0 ℃ was stirred 1 hour, suction filtration, and the sal epsom solid washs with the 200ml tetrahydrofuran (THF), triplicate.Tetrahydrofuran solution merges.Air distillation to 63 a ℃ left and right sides cut eliminates.Raffinate stirred 0.5 hour at 0 ℃, left standstill the 60ml water washing of suction filtration, solid, triplicate then 1.5 hours.Again with the washing of 60ml ethyl acetate, triplicate.Evaporate under the gained white powder solid room temperature dried, (S)-1,1-diphenylprolinol vitriol (38.1g, white solid) is from embodiment 1 to embodiment 3 overall yield 47%.
Embodiment 4:
In the 250ml round-bottomed flask, add (S)-1, and 1-diphenylprolinol vitriol (3.0g, 10mmol, 1.0eq), and the 10ml tetrahydrofuran (THF), (20mmol, 2.0eq), stirring at room to solid all dissolves 10ml sodium hydroxide (2M) aqueous solution.Add 40ml toluene, stirred 0.5 hour, cross and filter out emulsification, separatory, toluene are used the 5ml water washing once mutually.Remaining moisture is removed in distillation.The toluene solution of products obtained therefrom is directly used in embodiment 6 reactions.
ESI[M+1]＝254。
Embodiment 5
Under the nitrogen atmosphere, in the 500ml there-necked flask, add 250ml borine tetrahydrofuran (THF) (1M) solution, 40 ℃ of constant temperature water baths.System is the constant voltage system.Logical people 0.2g CO (carbon monoxide converter) gas is got rid of nitrogen in system, and the adding lithium borohydride (0.03g, 0.00125mol, 0.005eq).System is an enclosed system afterwards.Feed carbon monoxide in reaction system, reaction pressure 1.5atm stirs, and reaction system begins to absorb carbon monoxide, and reaction in 4 hours finishes, the shared carbon monoxide 7.2g that goes.79～81 ℃ of cuts are collected in rectifying, get methyl boron acid anhydrides (9.1g, productive rate 87%.Colourless liquid).
EI：126，111
1H?NMR(300MHz，CDCl3)：0.25～0.30(br?s，9H)
11B?NMR(300MHz，CDCl3)：32.5(s)。
Embodiment 6
Under the nitrogen atmosphere, the 100ml three-necked bottle is installed water trap, in the 100ml three-necked bottle, add 20ml (S)-1,1-phenylbenzene Prolinol (2.5g, 10mmol, 1.0eq) toluene solution, the methyl boron acid anhydrides that splashes into to reaction system in the control 15min (1.0g, 8mmol, 0.8eq), there is insolubles to occur, system temperature rises 10 ℃, and 25 ℃ were stirred 1 hour, and 130 ℃ of systems when being distilled to the reaction solution volume and being 5ml are cooled to 60 ℃, add 15ml toluene, 130 ℃ obtain concentration when being distilled to the reaction solution volume for 10ml and are about 1M target product (S)-2-methyl-CBS-oxazole borine (I) toluene solution; Remove whole toluene postcooling as steaming and obtain (S)-2-methyl-CBS-oxazole borine to room temperature.Get 2.0mg (S)-2-methyl-CBS-oxazole borine sample nmr analysis.Being somebody's turn to do (S)-2-methyl-CBS-oxazole boron and toluene solution thereof directly uses in embodiment 7 as the CBS catalyzer.
Mass spectroscopy (EI): 277
1H?NMR(300MHz，CDCl3)：87.62～7.13(m，10H)，4.34(dd，J＝5.8，9.6Hz，1H)，3.36～3.33(m，1H)，3.08～3.04(m，1H)，1.80～1.56(m，3H)，0.90～0.70(m，1H)，0.40(s，3H)；
11B?NMR(300MHz，CDCl3)：δ34.3
Concentration determination: 0.98mol/L
Embodiment 7
Add (S)-2-methyl-CBS-oxazole boron toluene solution (embodiment 6 preparations) 1ml under the nitrogen atmosphere in the 50ml three-necked bottle, the borine tetrahydrofuran solution 13ml stirring at room of adding 1.1M 30 minutes.Reaction solution is chilled to-10 ℃, controls 4 hours and drips Propiophenone (1.3g, 10mmol, dichloromethane solution 10ml 1.0eq).Dropwise-10 ℃ of reactions 1 hour, add 20ml methyl alcohol cancellation reaction, rotary evaporation, the raffinate silica gel chromatography gets (R)-phenylpropyl alcohol 1.3g.Productive rate 100%.Excessive 96.8% (ee) of mapping.
Embodiment 8
Working method is identical with embodiment 1～4 and 6, is raw material with (R)-proline(Pro), obtains target product (R)-2-methyl-CBS-oxazole borine (I) and toluene solution thereof.
Mass spectroscopy (EI): 277
1H?NMR(300MHz，CDCl3)：δ7.62～7.12(m，10H)，4.30(dd，J＝5.9，9.8Hz，1H)，3.35～3.31(m，1H)，3.10～3.05(m，1H)，1.80～1.58(m，3H)，0.90～0.70(m，1H)，0.40(s，3H)；
11B?NMR(300MHz，CDCl3)：δ34.3
Adopt the method for embodiment 7 to analyze excessive 96.2% (ee) of mapping.
Claims (9)
1. the preparation method of (S) or (R)-2-methyl-CBS-oxazole borine and toluene solution thereof comprises the steps:
(1) (S)-proline(Pro) or (R)-proline(Pro) obtains (S)-proline(Pro)-N-formyl chloride (IV) or (R)-proline(Pro)-N-formyl chloride (V) with the tetrahydrofuran solution reaction of triphosgene in tetrahydrofuran (THF):
(2) (S)-proline(Pro)-N-formyl chloride or (R)-proline(Pro)-N-formyl chloride in tetrahydrofuran (THF) with the triethylamine reaction, from reaction product, collect (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride (VI) or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride (VII) then;
(3) (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride reacts with phenyl grignard reagent in tetrahydrofuran (THF), reaction solution adds in the sulfuric acid, suction filtration, collect (S)-1,1-diphenylprolinol vitriol (VIII) and (R)-1,1-diphenylprolinol vitriol (IX);
(4) (S)-1,1-diphenylprolinol vitriol or (R)-1, the tetrahydrofuran (THF) suspension liquid of 1-diphenylprolinol vitriol and aqueous sodium hydroxide solution reaction, adopt toluene from reaction product, to extract collection (S)-1 then, 1-diphenylprolinol (X) toluene, tetrahydrofuran solution and (R)-1,1-diphenylprolinol (XI) toluene, tetrahydrofuran solution, cut below 85 ℃ in the reaction product is removed in air distillation then, obtain (S)-1,1-diphenylprolinol (X) toluene solution and (R)-1,1-diphenylprolinol (XI) toluene solution;
(5) carbon monoxide and borine tetrahydrofuran solution react under catalyst, and temperature of reaction is 20～45 ℃, and the reaction times is 2～12 hours, and reaction pressure is 1～2atm, and after reaction finished, methyl boron acid anhydrides (III) was collected in rectifying;
(6) (S)-1 of methyl boron acid anhydrides and step (4) acquisition, the toluene solution of 1-diphenylprolinol or (R)-1, the reaction of 1-diphenylprolinol toluene solution, obtain target product: (S)-toluene solution of 2-methyl-CBS-oxazole borine (I) or (S)-2-methyl-CBS-oxazole borine (I), or (R)-toluene solution of 2-methyl-CBS-oxazole borine (II) or (R)-2-methyl-CBS-oxazole borine (II).
2. method according to claim 1 is characterized in that, in the step (1), (S)-mol ratio of proline(Pro) or (R)-proline(Pro) and triphosgene is 1: 0.35～0.70; Reaction times is 1～3 hour, and temperature of reaction is 15～40 ℃.
3. method according to claim 1, it is characterized in that in the step (2), temperature of reaction is-5～5 ℃, reaction times is 0.5～1.0 hour, (S)-and the mol ratio of proline(Pro)-N-formyl chloride or (R)-proline(Pro)-N-formyl chloride and triethylamine is 1: 1.0～1.1.
4. method according to claim 1, it is characterized in that, in the step (3), temperature of reaction is-4 ℃～-10 ℃, reacted 2.5～8 hours, continue reaction 0.5～7 hour at 20～30 ℃ then, the preferred phenyl-magnesium-chloride of said phenyl grignard reagent, the molar weight of its adding is 250～350% of (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride; Said vitriolic concentration is 1.8～2.2M, and the molar weight that vitriolic adds is 350～450% of (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride.
5. method according to claim 1 is characterized in that, in the step (4), the mole dosage of sodium hydroxide is (S)-1,1-diphenylprolinol vitriol or (R)-1,100～300% of 1-diphenylprolinol vitriol.
6. method according to claim 1 is characterized in that, the mole dosage of carbon monoxide is 100～120% of a borine.
7. method according to claim 1 is characterized in that, (S)-1 in the step (6), 1-diphenylprolinol or (R)-1,1-diphenylprolinol and methyl boron acid anhydrides and mol ratio be 1: 0.3～1.0.
8. the preparation method of a methyl boron acid anhydrides, comprise the steps: that carbon monoxide and borine tetrahydrofuran solution react under catalyst, temperature of reaction is 20～45 ℃, reaction times is 2～12 hours, reaction pressure is 1.0～2.0atm, reaction obtains methyl boron acid anhydrides (III) from reaction product rectifying after finishing;
Said catalyzer is selected from a kind of of lithium borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE, tetrabutyl hydroboration amine, and consumption is 5～10% of a borine weight.
9. (S)-1,1-diphenylprolinol (X) toluene solution or (R)-1, the preparation method of 1-diphenylprolinol (XI) toluene solution comprises the steps: that (1) is (S))-proline(Pro) or (R)-proline(Pro) obtains (S)-proline(Pro)-N-formyl chloride (IV) or (R)-proline(Pro)-N-formyl chloride (V) with the tetrahydrofuran solution reaction of triphosgene in tetrahydrofuran (THF):
(2) (S)-proline(Pro)-N-formyl chloride or (R)-proline(Pro)-N-formyl chloride in tetrahydrofuran (THF) with the triethylamine reaction, from reaction product, collect (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride (VI) or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride (VII) then;
(3) (S)-proline(Pro)-N-carboxyl ring inner-acid anhydride or (R)-proline(Pro)-N-carboxyl ring inner-acid anhydride reacts with phenyl grignard reagent in tetrahydrofuran (THF), reaction solution adds in the sulfuric acid, suction filtration, collect (S)-1,1-diphenylprolinol vitriol (VIII) and (R)-1,1-diphenylprolinol vitriol (IX);
(4) (S)-1,1-diphenylprolinol vitriol or (R)-1, the tetrahydrofuran (THF) suspension liquid of 1-diphenylprolinol vitriol and aqueous sodium hydroxide solution reaction, adopt toluene from reaction product, to extract collection (S)-1 then, 1-diphenylprolinol (X) toluene, tetrahydrofuran solution and (R)-1,1-diphenylprolinol (XI) toluene, tetrahydrofuran solution, cut below 85 ℃ in the reaction product is removed in air distillation then, obtain (S)-1,1-diphenylprolinol (X) toluene solution and (R)-1,1-diphenylprolinol (XI) toluene solution.
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| CN110330520A (en) * | 2019-06-05 | 2019-10-15 | 南京康立瑞生物科技有限公司 | A kind of synthetic method of methyl boron anhydride compound |
| CN113943317A (en) * | 2021-10-31 | 2022-01-18 | 大连双硼医药化工有限公司 | Preparation method of MeCBS solid |
| CN113943317B (en) * | 2021-10-31 | 2024-02-27 | 大连双硼医药化工有限公司 | Preparation method of MeCBS solid |
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