CN1188479A - Process for preparing 1-[3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanone derivatives - Google Patents

Abstract

The present invention relates to a novel process for the preparation of 1-(3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanones from 1-halo-3-trialkylsilanyl-benzenes. 1-(3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanones are useful for the treatment of Alzheimer's disease and senile dementia. In addition, the present invention relates to a novel process for purifying 1-(3-trialkylsilylphenyl)-2,2,2-trifluoromethyl ethanones utilizing a novel extraction method.

Description

A kind of preparation 1-(3-trialkylsilkl phenyl)-2,2, the method for 2-trifluoromethyl ethanone derivatives

The present invention relates to a preparation 1-(3-trialkylsilkl phenyl)-2,2, the novel method of 2-trifluoromethyl ethanone.1-involved in the present invention (3-trialkylsilkl phenyl)-2,2, the 2-trifluoromethyl ethanone is described in European patent No.0409676 (on January 25th, 1991 is open), and people such as Schirlin report that this compound is used in particular for treating degenerative brain disorder and senile dementia.

The invention provides the novel method of the compound shown in the preparation formula (I): R wherein ₁, R ₂, R ₃Be C independently ₁～C ₄Alkyl.It may further comprise the steps: a) add the compound shown in the normal formula (II) in the mixture of an excessive magnesium in a kind of suitable organic solvent:

Wherein X represents Cl, Br or I; R ₁, R ₂And R ₃Define the same; B) add excessive trifluoracetic acid lithium then; C) add a kind of suitable reaction terminating agent then.The present invention also provides the novel method of the compound shown in the purification formula (I):

R wherein ₁, R ₂, R ₃Be mutual incoherent C ₁～C ₄Alkyl.It may further comprise the steps: a) approximately respectively be the suitable organic solution of the compound shown in the mixed solution washing type (I) of 50% methanol with concentration expressed in percentage by volume; B) with the mixed solution extraction step of the methanol suitable organic solution in a), wherein the concentration expressed in percentage by volume of first alcohol and water is about 80% and 20% respectively in the mixed solution; C) extraction liquid of methanol to the concentration expressed in percentage by weight of the compound shown in its Chinese style (I) is about 13%～18% enrichment step b); D) with the mixed solution that concentrated in a kind of suitable organic solvent extraction step c).

Used noun " C among the present invention ₁～C ₄Alkyl " be meant the alkyl of the straight or branched of 1 to 4 saturated carbon atom.The scope that is comprised is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and similar group.Noun " halogen ", " halogen " or " halogenide " used among the present invention are meant chlorine atom, bromine atoms or iodine atom.Used noun " Pfaudler reactor " is meant a kind of lass lining steel reactor well known to those skilled in the art among the present invention.Noun used in the present invention " baffle plate " is meant the object that is fixed on inside reactor in order to increase each material mixing in turbulent flow and then the promotion reactor.

Reaction formula I has summarized the preparation method of the starting raw material shown in the formula (II).All substituting groups, except other adds datedly, definition is the same.Reagent and starting raw material obtain for those skilled in the art easily.

Reaction formula I

In reaction formula I, the compound shown in the formula (II) is made under following condition by the dihalo compound shown in the formula (III):

Dihalo thing shown in the formula (III) is at a kind of rare gas element, as under the protection of nitrogen gas and Mg, and ClSiR ₁R ₂R ₃With a kind of suitable organic solvent chemical combination.Preferred all reagent and starting raw material all are actually anhydrous.Dihalo thing example shown in the formula (III) can select 1 for use, 3-dibromobenzene, 1, and 3-dichlorobenzene, 1-chloro-3-bromobenzene, 1,3-diiodo-benzene, 1-chloro-3-iodobenzene and 1-bromo-3-iodobenzene, the dihalo compound shown in the preferred formula (III) is 1, the 3-dibromobenzene.With respect to the dihalo compound shown in the formula (III), the total yield of the Mg of input is about 0.9～1.1 equivalent in the route shown in the reaction formula I, preferred 1 equivalent.In addition, be applicable to that the magnesium of grignard reaction is preferably as magnesium powder, magnesium grain, magnesium rod, magnesium chips and analogue, most preferably magnesium chips.Agitator of reactor configurations is as the swept-back wing agitator.Stirring velocity is fixed on one to be enough to provide on the well-mixed speed.In the process shown in the reaction formula I, with respect to the dihalo compound shown in the formula (III), the ClSiR of input ₁R ₂R ₃Total yield be about 0.8～1.2 equivalent, preferred 1.1 equivalents.ClSiR ₁R ₂R ₃Can select chlorotriethyl silane, three normal propyl chloride silane, three n-butyl chloride silane, dimethyl ethyl chlorosilane, dimethyl isopropyl chloride silane, trimethylchlorosilane and similar compounds for use.Preferred ClSiR ₁R ₂R ₃It is trimethylchlorosilane.In the process shown in the reaction formula I, the mass ratio of the dihalo compound shown in suitable organic solvent and the formula (III) is about 3～10, and preferred 4.6.For example, in as described in Table 1 second batch, use 810 pounds of toluene and 176 pound 1, the mass ratio of 3-dibromobenzene gained is 4.6 (810 pounds/176 pounds).The example of suitable organic solvent can be selected benzene, ethylbenzene, dimethylbenzene, diethylbenzene, toluene and similar compounds for use.Preferred organic is a toluene.Said mixture heats under about 20 ℃～80 ℃ temperature, and the temperature of preferred mixture is about 50 ℃.When the temperature of mixture begins to descend, add suitable ether.Suitable ether has ether, tetrahydropyrans, tetrahydrofuran (THF) and similar compounds.Preferred ether is tetrahydropyrans and tetrahydrofuran (THF), most preferably tetrahydrofuran (THF).In the process shown in the reaction formula I, with respect to the dihalo compound shown in the formula (III), the total yield of the suitable ether of adding is about 1.8～4 equivalents, preferred 2.5 normal ethers.Preferred total amount 2%～15% preferred 10%, suitable ether join in the mixture in the first batch.Remaining suitable ether with about 0.15～2 equivalent/hour speed join in the mixture, preferred speed be 0.7～1.2 equivalent/hour, most preferably be 1.13 equivalents/hour.The rate of addition of the suitable ether that control is remaining remains on the temperature of reaction mixture, 50 ℃ of for example preferred temperature with control reaction temperature.Preferably in dripping the ether process temperature maintenance of the method for reaction formula I at about 50 ℃.After suitable ether added, reaction solution stirred 10～15 hours at about 20 ℃～70 ℃, and preferred temperature is 50 ℃.Under agitation, reacting slurry joins temperature carefully and is about in 5 ℃～50 ℃ the water.Compound shown in the formula (II) can be by some technology separation and purification of knowing, as extraction, distillation, chromatography and similar method.For example, mixture stirs and separates each phase after 10 minutes to 1 hour, and organic phase also can wash with water once more.Use a kind of suitable siccative then, as anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure obtains formula (II) compound, and this compound can be by technology well known in the art, as chromatography with or underpressure distillation be further purified.

Reaction formula II

Reaction formula II has described method of the present invention.Except other adds datedly, the definition of all substituting groups is the same, and reagent and starting raw material can obtain easily to those of ordinary skills.

In reaction formula II, at a kind of rare gas element, under protection of nitrogen gas, to a suitable reactor that swept-back wing agitator and baffle plate are housed, as adding the excessive magnesium that is suitable for carrying out grignard reaction in the Pfaudler reactor of 200 gallons of exsiccant.Preferred 1.0 normal magnesium add in the suitable reactor, most preferably 1.05 normal magnesium.The example that is suitable for the magnesium of grignard reaction has magnesium powder, magnesium grain, magnesium rod, magnesium chips and analogue, preferred magnesium chips.In reactor, add about 10 normal ethers then.Suitable ether has ether, tetrahydropyrans, tetrahydrofuran (THF) and similar compounds, preferred tetrahydrofuran (THF).Ether must be anhydrous, and wherein the content of water had better not surpass 100ppm.Heated mixt under 30 ℃～55 ℃ temperature, preferred temperature is 45 ℃.In mixture, add about 0.02 to 0.10 normal suitable initiator then, as glycol dibromide.Preferably approximately 0.04 normal glycol dibromide joins in the mixed solution in about 45 ℃.After adding suitable initiator, show that when having observed exothermic phenomenon reaction has been initiated.When temperature-stable during, in reactor, add the suitable 1-halogen-3-trialkylsilkl-benzene shown in 1 equivalent formula (II) 45 ℃ of left and right sides.Suitable 1-halogen-3-trialkylsilkl-benzene needs slowly to add until the beginning heat release, adds this 1-halogen-3-trialkylsilkl-benzene with the speed that can keep temperature of charge to be lower than about 58 ℃ then, and preferred temperature is lower than 50 ℃.The example of the 1-halogen-3-trialkylsilkl-benzene that is suitable for has 1-bromo-3-trimethyl silyl-benzene, 1-chloro-3-trimethyl silyl-benzene, 1-iodo-3-trimethyl silyl-benzene, 1-bromo-3-triethylsilyl-benzene, 1-bromo-3-three n-propyl silyl-benzene, 1-bromo-3-dimethylethylsilyl-benzene, 1-bromo-3-dimethyl sec.-propyl silyl-benzene, 1-bromo-3-three normal-butyl silyl-benzene and similar compounds.The preferred 1-halogen-3-trialkylsilkl-benzene that is suitable for is 1-bromo-3-trimethyl silyl-benzene.In addition, also the suitable 1-halogen-3-trialkylsilkl-benzene shown in 1 equivalent formula (II) can added slowly carefully in the mixture of the suitable ether of Mg/ directly under the condition that does not add suitable initiator.Yet do not have suitable initiator in reaction time operation must SC, can cause a uncontrollable reaction because added the 1-halogen-3-trialkylsilkl-benzene shown in a large amount of formulas (II) before causing heat release.After 1-halogen-3-trialkylsilkl-benzene added, reaction mixture was incubated 2～4 hours about 45 ℃, preferred 3 hours this.Then reaction mixture is cooled to-12 ℃～0 ℃ approximately, preferred temperature is 0 ℃.Add excessive trifluoracetic acid lithium with the speed that keeps reacting liquid temperature to be lower than about 10 ℃ in reaction mixture then, preferred about 1.3 normal trifluoracetic acid lithiums add in the reaction mixture, most preferably about 1.1 equivalents.In addition, about 1.1 normal trifluoracetic acid lithiums are preferably earlier at a suitable charging reaction device, as mixing with 10 normal appropriate organic solvent in 50 gallons of enamel reactors of an exsiccant, and with 90 rev/mins speed stir about 2～4 hours.Appropriate organic solvent has tetrahydrofuran (THF), ether, tetrahydropyrans, dioxane and similar compounds.Preferred organic is a tetrahydrofuran (THF).Most preferably from about 1.1 equivalent trifluoracetic acid lithiums mix with appropriate organic solvent.The mixing solutions of preferred this suitable organic solvent/trifluoracetic acid lithium must be anhydrous before adding reaction mixture.Can be lower than 200ppm with mixing solutions content of water in solution of this suitable organic solvent/trifluoracetic acid lithium of 3A molecular sieve drying.In reaction mixture, add this solution with the speed that can keep reacting liquid temperature to be lower than about 10 ℃ then.Reaction mixture is again 12 ℃ of left and right sides stir abouts 30 minutes.Then, at a kind of suitable reaction terminating device, as adding a kind of suitable reaction terminating agent in the Pfaudler reactor that swept-back wing agitator and baffle plate be housed.Suitable reacting terminating solution has aqueous hydrochloric acid, aqueous sulfuric acid, aqueous hydrochloric acid/heptane, water/37% hydrochloric acid/Glacial acetic acid/heptane and similar solution, preferably water/37% hydrochloric acid/Glacial acetic acid/heptane.In addition, special again preferred weight percentage composition is about 73% water, 2% hydrochloric acid (37%), water/37% hydrochloric acid of 6% Glacial acetic acid and 19% heptane/Glacial acetic acid/heptane reaction terminating agent.Suitable reaction terminating agent will be chilled to earlier below 5 ℃ before adding reaction mixture, then can keep the speed that mixture temperature is lower than about 15 ℃ in the reaction terminating device to add reaction mixture in suitable reaction terminating agent.After adding, 200 gallons reactor is with suitable organic solvent such as tetrahydrofuran (THF) drip washing, and organic leacheate is added in the terminator.Mixed solution in the reaction terminating device was 15 ℃ of left and right sides stir abouts 15 minutes.After stopping to stir, mixture left standstill about 40 minutes.Water layer below decant goes out from the reaction terminating device, top organic layer are transferred in the suitable reactor, and the enamel reactor of for example using one 200 gallons is as middle storage tank.

Those of ordinary skill in the art can know, if the starting raw material shown in the formula of using among the reaction formula II (II) is polluted by the organic halogen of unwanted phenyl-dihalide class, for example 1,3-dibromobenzene, 1,3-dichlorobenzene, 1-chloro-3-bromobenzene, 1,3-diiodo-benzene, 1-chloro-3-iodobenzene and 1-bromo-3-iodobenzene, so in the route shown in the reaction formula II, for in the starting raw material whenever the amount unwanted phenyl-dihalide, in step a, to add two normal magnesium, and in step b, will add two normal trifluoracetic acid lithiums.For example, if contain in the starting raw material by 0.10 mole 1,1 mole of 1-bromo-3-trimethyl silyl-benzene that the 3-dibromobenzene pollutes under optimal conditions, must use 1.25 moles of magnesium at step a, and must use 1.30 moles of trifluoracetic acid lithiums at step b so.Technology and method that the content of unwanted phenyl-dihalide is known in this area are easily come out as gas chromatographic detection.

For any one synthetic route, be accompanied by the purpose compound and always generate unwanted by product of all kinds.Therefore resulting thick product preferably carries out purifying to remove unwanted by product.For example, the thick product shown in the formula (I) can carry out purifying by the new-type extracting process shown in the reaction formula III.Unless otherwise noted, all substituting group definition are the same.Reagent used in the extraction can obtain easily to those of ordinary skills.

The reaction formula III

In steps A, the water layer that decant comes out in the process shown in the reaction formula II reinstalls in the reaction terminating device and with a kind of appropriate organic solvent and extracts.The organic solvent that is suitable for has heptane, ether, hexane, toluene, dimethylbenzene and similar solvent, preferred heptane.Water below decant goes out from the reaction terminating device is in 200 gallons the reactor of packing into after top organic extract liquid and primary organic layer (obtaining in the process shown in the reaction formula II) merging.Organic layer after concentrating under reduced pressure merges to the compound shown in the formula (I) in this appropriate organic solvent, reach about 30%～35% as the weight percent in the heptane.In step B, organic solution respectively is 50% methanol mixed solution washing 2～3 times with volume percent, preferably washs 3 times.This step washing process can be removed the unwanted by product shown in the formula (IV).In step C, organic solution is respectively 80% and 20% methanol mixed solution extraction 3～7 times with the concentration expressed in percentage by volume of first alcohol and water, preferred 5 times.The compound of step C shown in can wushu (I) separates by extraction process with the unwanted by product shown in the formula V.Merge the extraction liquid of methanol then and be evaporated to the compound concentrations shown in the solution Chinese style (I) and reached for about 13%～18% (being divided into two-phase) at this concentration solution.In step D, the methanol layer after concentrating with the extraction of a kind of appropriate organic solvent 1～2 time.The organic solvent that is suitable for has heptane, ether, toluene, hexane and similar solvent, preferred heptane, preferred 2 times of extraction times.Merge organic phase and concentrating under reduced pressure and obtain the 1-shown in the formula (I) (3-trialkylsilkl phenyl)-2,2,2-trifluoromethyl ethanone derivatives.Compound shown in the formula (I) each stage of above-mentioned extraction and purifying all exist and formula (Ia) shown in hydrate and the balance between the hemiketal shown in the formula (Ib).Can be by means commonly known in the art, as molecular sieve, distillation, component distillation and under various pressure heating impel this balance to transform to the direction of complete production (I).Ratio those of ordinary skill in the art between the hemiketal shown in hydrate shown in purpose compound shown in the formula (I) and the formula (Ia) and the formula (Ib) can be by detecting as vapor-phase chromatography.Necessary, the compound shown in the formula (I) can be further purified as chromatography and/or distillation method by technology well known to those skilled in the art.

Following example has been represented the typical synthetic method described in reaction formula I and the reaction formula II.It only is explanation the present invention that these examples are interpreted as, and and do not mean that and limit scope of the present invention by any way.Here the implication of the following term of Shi Yonging is respectively: " ppm " be meant 1,000,000/; " g " is meant gram; " mmol " is meant mmole; " L " is meant liter; " ml " is meant milliliter; " bp " is meant boiling point; " mp " is meant fusing point; " ℃ " be meant centigradetemperature; " mm Hg " is meant mmhg; " μ L " is meant microlitre; " μ g " is meant microgram; " μ M " is meant every liter of micromole; " eq " is meant equivalent; " min " is meant minute; " rpm " is meant revolution/per minute; " THF " is meant tetrahydrofuran (THF); " LiTFA " is meant the trifluoracetic acid lithium; And " lb " is meant pound.

Example 1

The a small amount of preparation of 1-bromo-3-trimethyl silyl benzene

Reaction formula 1; Feed hopper, mechanical stirrer, reflux condensing tube and a heat-sensitive recorder are installed on a trough of belt line and thermosensitive thermometer telescopic 500ml three-necked round bottom flask.Feed nitrogen in the bottle, add Mg (4.84 grams, 0.199 mole) then, trimethylchlorosilane (45.9 grams, 0.422 mole), toluene (214 gram) and 1,3-dibromobenzene (46.5 grams, 0.197 mole).With heat gun heated mixt to 50 ℃, it is slowly cooled off.When temperature begins to descend, add tetrahydrofuran (THF) (38.1 gram).Temperature continues to reduce to 42 ℃, and keeps stable, begins then to rise.Drip remaining tetrahydrofuran (THF) (342.9 gram), dripped one in per 5～8 seconds, make temperature be controlled at 50 ± 2 ℃, dripped 2 hours.Heat release was slowed down after tetrahydrofuran (THF) when about 60%～70% added, and generated cotton-shaped solid.Remaining tetrahydrofuran (THF) adds fast and does not have an exothermic phenomenon.Mixture placed to spend the night reduce to room temperature.Reaction soup compound vacuum transfer to is equipped with in 1 liter of flask of 50 ℃ of hot water, and temperature is risen.Stirred the mixture 10 minutes, and separated each phase (mixture temperature is 45 ℃ during separation) then.Organic phase washes (50ml) with water, with anhydrous magnesium sulfate/dried over sodium sulfate, filters, concentrating under reduced pressure, and the concentric tube distillation column with theoretical plate number 40 distills under 15mmHg, the purpose compound is 94～105 ℃ of collections, be a kind of colourless oil (32.7 grams, 76.8%).

The reversed-phase HPLC (high performance liquid chromatography) that can utilize following instrument to carry out the purpose compound is analyzed: a Hitachi L-6200 type gradient pump; Perkin-Elmer 235 type diode array detectors; Spectra-Physics 4270 type totalizing instruments; A Hitachi AS-2000 type automatic sampler; With Rheodyne 7125 type sampling valves of being furnished with one 20 μ L sample hose and Zorbax 4.8 * 80mm ODS chromatographic column (granularity 5 μ m).The detector wavelength is set to 255nm; Moving phase is 90: 10 acetonitrile/water, and flow velocity is set to 2ml/min; The retention time of purpose compound (Rt) is about the 0.92-0.95 branch.

The preparation LC (liquid chromatography) of purpose compound can utilize following instrument to realize: Gilson 305 type pumps of being furnished with Gilson Manometric Module Model 805; A LinearUV-106 type detector (254nm); A Sargent-Welch SRG-2 type chart recording instrument; With Rheodyne 7125 type sampling valves of being furnished with a 1.0ml sample introduction pipe and Alltech 22.5 * 250mmEconosphereC18 chromatographic column (granularity 10 μ m).Crude product dissolves with acetonitrile before sample introduction.The detector wavelength is set to 254nm, and moving phase can be the acetonitrile/water of 90: 10 or 85: 15, and flow velocity is set to 15ml/min, and the retention time scope of purpose compound is about 8.5-11 minute.

Can carry out the gas chromatographic analysis of purpose compound by following instrument: a HewlettPackard 5890A type gas chromatograph; A Hewlett Packard7573A type automatic sampler of being furnished with 10 μ L sample introduction needle; Hewlett Packard 7673 type automatic sampler pallets; A flame ionization detector; A PE-NelsonAccessChrom Rev.1.9 who is furnished with 941 A/D data logging totalizing instruments.Film is thick to be Supelco SPB-130m * 0.32mmID chromatographic column (downcutting from 60 meters long posts) of 1 micron.With the helium is carrier gas.Working conditions is: column cap is pressed 10psi, shunting 105ml/min, column flow rate 1.8ml/min, detector replenishes nitrogen flow rate 20ml/min, detector hydrogen flow rate 20ml/min, detector air velocity 300ml/min, the detector range is 2,275 ℃ of sampler temperature, 300 ℃ of detector temperatures.The thermograde program is 60 ℃ of initial temperatures, rises to 130 ℃ with the speed of about 16 ℃/min, keeps 12 minutes at 130 ℃ then, and the speed with about 22 ℃/min rises to 320 ℃ at last, and finishes operation.The retention time of 1-bromo-3-trimethyl silyl benzene is about 16 minutes.

Example 1a provides a method in common, has prepared a large amount of 1-bromo-3-trimethyl silyl benzene of 10 different batches according to this method.The table 1 of example 1a back has been summed up the reagent that uses in 10 different batches and the quantity and the result of raw material.

Example 1a

A large amount of preparations of 1-bromo-3-trimethyl silyl benzene

Reaction formula I; In 200 gallons of enamel reactors that the swept-back wing agitator is housed, add magnesium chips (18.25 pounds).Purging with nitrogen gas is used in reactor sealing, pressure measurement then.Add 1 in the vacuum downhill reaction device, 3-dibromobenzene (176 pounds), vacuum adds toluene (806.6 pounds) then.Agitator speed is set to 130 rev/mins to obtain the good mixing effect.In the batch can that trimethylchlorosilane is housed, feed nitrogen pressure, and batch can is communicated with the reactor head space, make trimethylchlorosilane (180 pounds) inflow reactor.Dress is used the purging with nitrogen gas line of pipes after finishing trimethylchlorosilane.Reactor temperature control system is set makes the interior temperature of reactor maintain 50 ℃.When the interior gentle jacket temperature of reactor is stabilized in 50 ℃, pump into tetrahydrofuran (THF) (14 pounds) to the reactor head space.The monitoring reaction actuator temperature is to determine the beginning of reaction (heat release).When temperature in the reactor is higher than 5～10 ℃ with the jacket temperature temperature difference, can think that reaction begins.After the reaction beginning, with about 0.7～1.2 equivalent/hour speed in reactor, pump into tetrahydrofuran (THF) (130 pounds).After adding tetrahydrofuran (THF), continued stirred reaction mixture 10～15 hours down at 50 ℃.

Reaction mixture is transferred to 300 gallons of enamel reactors that pitched blade agitators and water (5～10 ℃, 100 gallons) are housed.Toluene (about 20 pounds) is added just now 200 gal reactor under vacuum, and wash line of pipes between 200 gal reactor and 300 gal reactor with it.300 gal reactor stir abouts 1 hour stop to stir then, and reaction mixture was placed about 30～60 minutes.From 300 gal reactor, discharge water, and then add entry (about 25 gallons), stirred about 30 minutes.Stop to stir, reaction mixture was placed about 30～90 minutes, discharged water from 300 gal reactor.Organic phase is disposed in 55 gallons of batch cans then.300 gal reactor are carried out pressure test, use purging with nitrogen gas.With about 1600～2000 pounds above-mentioned organic solution from 55 gallons batch can vacuum transfer to reactor.Agitator speed is set to about 100 rev/mins, jacket temperature is set is higher than in the reactor 10～20 ℃ of temperature with the retaining clip sleeving temperature, begins to steam volatile matter to the cut receptor.Along with the liquid level in the reactor descends, from 55 gallons batch can, add organic solution, add five batches altogether.Continue distillation temperature rise to 68 in reactor～72 ℃.Reactor jacket temperature is set then is about 25 ℃, charge into nitrogen, remove vacuum.When temperature in the reactor is lower than 35 ℃ of left and right sides, open manhole, to reactor, add diatomite (about 20 pounds) and sal epsom (about 20 pounds) from manhole.Close manhole and carry out pressure test, feed nitrogen then.Reaction content is discharged into by a Nutsche strainer (by add a new filter cloth preparation in the bottom) in 55 gallons the batch can, obtains the purpose compound.

Each productive rate of reaction conditions of table 1.1-bromo-3-trimethyl silyl benzene, totally ten batches, every batch according to the similar approach preparation of method described in the embodiment 1

	??#1	??#2	??#3	??#4	??#5	??#6	??#7	??#8	??#9	??#10	????total
												Magnesium (lb)	??18.25	??18.25	??18.25	??18.25	??18.25	??18.25	??18.3	??18.5	??18.3	??17.5	????182
1,3-dibromobenzene (lb)	??176	??176	??176	??176	??176	??176	??176	??176	??176.3	??168.9	????1753
												Toluene (lb)	??806.6	??810	??811	??812	??810	??811	??810	??810	??814	??780	????8075
Trimethylchlorosilane (lb)	??176	??180	??178	??159	??176	??171	??172	??215	??177	??138	????1742
												Initial THF (lb)	??28	??14	??14	??14	??14	??14	??14	??14	??14.1	??13.3	????153
Final THF (lb)	??116	??130	??130	??130	??130	??130.1	??130	??130	??120	??125	????1271
												Total THF (lb)	??144	??144	??144	??144	??144	??144.1	??144	??144	??144.1	??138.3	????1434.5
The final THF joining day (min)	??140	??180	??140	??145	??145	??135	??160	??194	??210	??215
												Stop water (gal)	??100	??100	??100	??100	??100	??100	??100	??100	??100	??100	????1000
Toluene flushing (lb)	??21.5	??20	??20	??20	??20	??20	??20	??28	??20	??21	????211
												Washing sh (gal)	??25	??25	??25	??25	??25	??25	??25	??25	??25	??25	????250
Stirring velocity (rpm)	??130.4	??130.8	??130	??110	??110	??135	??133	??135	??132.5	??127
												The productive rate (%) of 1-bromine 3-trimethyl silyl benzene	??64.58	??68.78	??63.93	??64.90	??63.53	??64.39	??64.35	??63.40	??66.20	??66.04	????65.0

Example 2

The preparation of 1-chloro-3-trimethyl silyl-benzene Reaction formula I; 1-chloro-3-trimethyl silyl-benzene is to utilize with the similar method of example 1 and the described method of the described method of example 1a to make with trimethylchlorosilane with as the 1-chloro-3-bromobenzene of the dihalo thing shown in the formula (III).

Example 3

The preparation of 1-bromo-3-trimethyl silyl-benzene

Reaction formula I; 1-bromo-3-trimethyl silyl-benzene is to utilize with the similar method of example 1 and the described method of example 1a to make with trimethylchlorosilane with as the 1-bromo-3-iodobenzene of the dihalo thing shown in the formula (III).

Example 4

The preparation of 1-chloro-3-trimethyl silyl-benzene

Reaction formula I; 1-chloro-3-trimethyl silyl-benzene is to utilize with the similar method of example 1 and the described method of example 1a to make with trimethylchlorosilane with as the 1-chloro-3-iodobenzene of the dihalo thing shown in the formula (III).

Example 5

The preparation of 1-iodo-3-trimethyl silyl-benzene Reaction formula I; 1-iodo-3-trimethyl silyl-benzene be utilize with the similar method of example 1 and the described method of example 1a with trimethylchlorosilane with as 1 of the dihalo thing shown in the formula (III), the 3-diiodo-benzene makes.

Example 6

The preparation of 1-bromo-3-triethylsilyl-benzene

Reaction formula I; 1-bromo-3-triethylsilyl-benzene be utilize with the similar method of example 1 and the described method of example 1a with 1,3-dibromobenzene and as Compound C lSiR ₁R ₂R ₃Chlorotriethyl silane make.

Example 7

The preparation of 1-bromo-3-three n-propyl silyl-benzene

Reaction formula I; 1-bromo-3-three n-propyl silyl-benzene be utilize with the similar method of example 1 and the described method of example 1a with 1,3-dibromobenzene and as Compound C lSiR ₁R ₂R ₃Three normal propyl chloride silane make.

Example 8

The preparation of 1-bromo-3-dimethylethylsilyl-benzene

Reaction formula I; 1-bromo-3-dimethylethylsilyl-benzene be utilize with the similar method of example 1 and the described method of example 1a with 1,3-dibromobenzene and as Compound C lSiR ₁R ₂R ₃The dimethyl ethyl chlorosilane make.

Example 9

The preparation of 1-bromo-3-dimethyl sec.-propyl silyl-benzene Reaction formula I; 1-bromo-3-dimethyl sec.-propyl silyl-benzene be utilize with the similar method of example 1 and the described method of example 1a with 1,3-dibromobenzene and as Compound C lSiR ₁R ₂R ₃Dimethyl isopropyl chloride silane make.

Example 10

The preparation feedback formula I of 1-bromo-3-three normal-butyl silyl-benzene; 1-bromo-3-three normal-butyl silyl-benzene be utilize with the similar method of example 1 and the described method of example 1a with 1,3-dibromobenzene and as Compound C lSiR ₁R ₂R ₃Three n-butyl chloride silane make.

Example 11a

1-(3-trimethyl silyl phenyl)-2,2, the preparation of 2-trifluoromethyl ethanone

Reaction formula II; 1 liter of three-necked round bottom flask, adding magnesium chips (11.9 grams, 0.49 mole) and the anhydrous tetrahydro furan (250 gram) of mechanical stirrer, temperature probe and nitrogen scatterer are housed with one of purging with nitrogen gas.Disposable adding glycol dibromide in mixture (2.4g, 0.0128 mole, DBE).Almost begin heat release immediately, temperature rises to 29 ℃.Temperature is reduced to after 25 ℃, adds 1-bromo-3-trimethyl silyl-benzene (80.63 grams, 0.352 mole, 80.63%) in 30 minutes.In adition process, temperature raises once more and is stabilized in 50 ± 2 ℃ with ice bath.Finish, the reaction solution heat release is slowed down, and mixture is spent the night 45 ℃ of insulated and stirred.Mixture is chilled to 0 ℃ then, in 30 minutes, adds tetrahydrofuran (THF) (250 gram) solution of trifluoracetic acid lithium (352 grams, 0.575 mole, 200ppm water), again mixture is warming up to room temperature.Under agitation condition, with mixture vacuum transfer to a water (583 gram), Glacial acetic acid (51 gram) is in the mixture of hydrochloric acid (27 grams, 37%) and heptane (142 restrain) and maintain the temperature at about 10～15 ℃.Finish, mixture is warming up to 20 ℃.Separate each layer, with heptane (50 gram) aqueous layer extracted.Organic layer and organic extract liquid merge back concentrating under reduced pressure (45 ℃ 45mmHg) reach 38.5% to concentration.Wash this solution with methanol (50/50, v/v, 4 * 185 grams), use methanol (80/20, v/v, 5 * 185 grams) extraction again.Portioning concentrating under reduced pressure behind the combining extraction liquid (45 ℃, 45mmHg).Use heptane (150 gram) extraction two-phase mixed solution then.The extraction liquid anhydrous magnesium sulfate drying filters back concentrating under reduced pressure (45 ℃ 45mmHg) obtain a lurid oil, i.e. target compound (78.2 grams, overall yield 77.5%).Target compound can be by a theoretical plate number 40 concentric tube distillation column distillation purifying (94～105 ℃, 15mmHg), the target compound that obtains is a colourless oil.

Example 11b provides a method in common, has prepared a large amount of 1-(3-trimethyl silyl phenyl)-2,2 of 10 different batches, 2-trifluoromethyl ethanone according to this method.The table 2 of example 11b back has been summed up 10 different batches and has been prepared 1-(3-trimethyl silyl phenyl)-2,2, the reaction conditions of 2-trifluoromethyl ethanone and yield percentage, and these 10 batches methods of describing according to example 11b are reacted in similar mode.

Example 11b1-(3-trimethyl silyl phenyl)-2,2, a large amount of preparations of 2-trifluoromethyl ethanone

Reaction formula II; 200 gallons of enamel Pfaudler reactor (being called reactor A) that swept-back wing agitator and baffle plate be housed and one 50 gallons enamel reactors (being called reactor B) carry out drying and vacuumize at 80 ℃, use purging with nitrogen gas again.From manhole adds magnesium chips (15.2 pounds) to reactor A after, add tetrahydrofuran (THF) (390 pounds) again.Tetrahydrofuran (THF) is wanted first sampling analysis, and water content can not surpass 100ppm.The agitator speed of reactor A is decided to be 100 rev/mins.The chuck of reactor A uses the control of slave mode temperature, and interior temperature set point is 45 ℃.When temperature in the reactor is stabilized in 45 ℃ of left and right sides, in reactor A, add about 2.8-3.6 pound glycol dibromide, with 3 pounds of tetrahydrofuran (THF) flushing filling tubes.Because heat release indicates reaction and is initiated, and therefore needs the monitoring jacket temperature.Be initiated and after the interior temperature of reactor A is stabilized in about 45 ℃, in reactor A, add 1-bromo-3-trimethyl silyl benzene (6～8 pounds) in reaction.Tetrafluoroethylene (Teflon) the surge pump control that drives with a nitrogen adds 1-bromo-trimethyl silyl benzene in reactor.Because heat release indicates reaction and is initiated, and therefore needs the monitoring jacket temperature.After reaction causes, in reactor A, add remaining 1-bromo-trimethyl silyl benzene (120～122 pounds), and temperature is lower than about 50 ℃ in keeping.Finish, with tetrahydrofuran (THF) (5 pounds) flushing filling tube.Mixed solution is chilled to about 0 ℃ after about 3 hours 45 ℃ of insulations.The trifluoracetic acid lithium (about 88 pounds, LiTFA) and tetrahydrofuran (THF) (about 300 pounds) adds in the reactor B and stirred about 2～4 hours with 90 rev/mins speed.Then, transfer to trifluoracetic acid lithium/tetrahydrofuran solution in the reactor A and keep the interior temperature of reactor A to be lower than about 10 ℃.When being lower than 10 ℃, the interior temperature that needs controlling reactor A can temporarily stop to shift.Finish, in reactor B, add tetrahydrofuran (THF) (about 64 pounds), then the tetrahydrofuran (THF) washing fluid is transferred in the reactor A.Mixture was 12 ℃ of stir abouts 30 minutes.In 300 gallons of enamel reactors (being called reactor C) that swept-back wing agitator and baffle plate be housed, add 37% hydrochloric acid (about 22 pounds), the reaction terminating agent of Glacial acetic acid (65 pounds) and heptane (190 pounds) composition by water (about 751 pounds).Reaction terminating agent is chilled to earlier and is lower than 5 ℃, the reaction mixture in the reactor A is transferred among the reactor C again, keeps the interior temperature of reactor C to be lower than about 15 ℃.Finish, in reactor A, add tetrahydrofuran (THF) (about 60 pounds), and then transfer among the reactor C.Mixture among the reactor C stirred 15 minutes about 15 ℃ at least, after stopping to stir, and solution left standstill at least 40 minutes.Following water layer is decanted in the batch can, and top organic layer is transferred in 200 gallons the enamel reactor (being called reactor D) as distillation receiving bottle and middle storage tank.The water that migrates out previously joins among the reactor C again, and extracts with heptane (100 pounds).The water of lower floor is discharged in the batch can, and top organic layer is transferred to reactor D, merges with primary organic layer.Organic layer concentrating under reduced pressure after the merging, PIP are 25mmHg, 25 ℃～30 ℃ of interior temperature, about 40 ℃～45 ℃ of jacket temperature.Solution concentration is to about 40 gallons.Solution after concentrating is transferred in the reactor B, and further is concentrated into the concentration expressed in percentage by weight of target compound in heptane and reaches 30%～35%.In order to reach this concentration, can add heptane when needed.This organic solution is with the mixture washing of methanol (50/50, v/v, 180 pounds) 3 times, and then with the mixture extraction of methanol (80/20, v/v, 190 pounds) five times.After the extraction liquid of methanol merged, at 25mmHg left and right sides concentrating under reduced pressure, interior temperature was about 20 ℃～25 ℃, was concentrated into target compound concentration in solution and was about 13%～18%, had two-phase to generate in this concentration.Methanol layer after concentrating heptane (250 pounds) extracting twice.After the heptane extraction liquid merged, concentrating under reduced pressure obtained target compound.

Target compound can be further purified by distillation.For example, separating the target compound (436 pounds) that obtains above joins under vacuum in 100 gallons the enamel reactor as matrass and reboiler.The distillation column of 4 inches thicknesses that are filled with 4 feet high structured packings and the head space of matrass join, and load onto reflux splitter and be used for cut and reflux or collect.With an area be 28 square feet hastelloy (Hastalloy) C type pipe in pipe as condenser, with one 50 gallons enamel reactors as the distillation collector.The agitator speed of matrass is set to 80 rev/mins.The retort clamp sleeving temperature is set in 150 ℃, with the maximum temperature difference of interior temperature can not be above 30 ℃.Collect the lower boiling fraction in about 150-200mmHg, temperature reaches 140 ℃ in matrass, and the product in the distillation receptor is released, and the temperature of matrass drops to and is lower than 50 ℃, and pressure drops to about 15mmHg.The jacket temperature of matrass is arranged on 150 ℃, and the maximum temperature difference between chuck and the Nei Wen is 30 ℃.The reflux ratio of reflux splitter is arranged on 3: 1～between 10: 1.Steaming removes lower boiling impurity and reaches about 100 ℃～105 ℃ until the temperature of overhead product.To distill the interior cut of collector then all pours out.Reflux ratio is set at 1: 1 or lower, steams target compound till no cut steams.Product in the distillation collector is transferred in the batch can be further purified target compound by one 0.1 micron Polish filter.If necessary, those of ordinary skill in the art can with the similar condition of above-mentioned condition under heavily steam.

Table 2.

Lot number/weight (lb)	??#1	??#2	??#3	??#4	??#5	??#6	??#7	??#8	??#9	??#10
											Magnesium	??15.3	??15.2	??15.2	??15.2	??15.2	??15.2	??15.2	??15.2	??15.2	??15.2
THF	??399	??398	??398	??398	??398	??398	??398	??399	??398	??400
											Glycol dibromide	??3.1	??3.5	??3.2	??3.4	??3	??3.6	??2.8	??3.5	??3.1	??3.5
1-bromo-3-trimethyl silyl benzene	??128	??128.2	??128.0	??128.0	??128.0	??128.0	??128.0	??128.0	??128.5	??128.0
											LiTFA	??88.7	??88.6	??87.8	??88.0	??88.0	??88.0	??88.0	??88.0	??88.0	??87.0
THF+LiTFA	??300	??301	??300	??300	??300	??301	??344	??300	??300	??300
											The adding of LiTFA/THF (min)	??60	??60	??59	??44	??60	??60	??65	??60	??55	??60
Reactor B THF drip washing	??64	??64	??64	??64	??64	??64	??64	??65	??65	??66
											Stop water	??909	??751	??751	??751	??751	??751	??751	??751	??751	??751
37％Hcl	??22	??22	??22	??22	??22	??22	??22	??22	??22	??22
											Glacial acetic acid	??63	??65	??65	??65	??65	??65	??65	??65	??65	??65
Heptane	??191	??190	??190	??190	??190	??190	??190	??190	??191	??196
											Add terminator (min)	??210	??25	??25	??25	??20	??20	??25	??12	??10	??20
Reactor A THF drip washing	??60	??60	??60	??60	??60	??60	??60	??60	??60	??60
											Purpose compound (wgt)	??70.9	??76.9	??77.7	??75.1	??82.7	??73.3	??69.7	??80.8	??77.4	??82.1
Yield percentage	??66.5	??72.0	??72.9	??70.4	??77.6	??68.7	??65.3	??75.8	??72.3	??77.1

Use Hewlett Packard 5890A type gas chromatograph that the target compound that final separation obtains is carried out gas chromatographic analysis, comprise a Hewlett Packard 7573A type automatic sampler of being furnished with 10 μ L sample introduction needle; Hewlett Packard 7673 type automatic sampler pallets; A flame ionization detector; Nelson AccessChrom data integrate instrument and film are thick to be Supelco SPB-1 30m * 0.32mm ID chromatographic column of 1 micron.With the helium is carrier gas.Working conditions is: column cap is pressed 10psi, shunting 105ml/min, column flow rate 1.8ml/min, detector replenishes nitrogen flow rate 20ml/min, detector hydrogen flow rate 20ml/min, detector air velocity 300ml/min, 275 ℃ of sampler temperature, 300 ℃ of detector temperatures.The thermograde program is 120 ℃ of initial temperatures, keeps 22 minutes, rises to till 320 ℃ with the speed of about 30 ℃/min.

The approximate retention time of the above-mentioned analytical procedure of table 3.

Compound	Retention time (branch)
		Tribromo-acetyl benzene	????3.1
2-chloro-p-Xylol	????6.0
		1-(3-trimethyl silyl phenyl) 2,2, the 2-trifluoromethyl ethanone	????10.0
1-(3-trimethyl silyl phenyl) 2,2,2-trifluoromethyl ethanone hemiketal	????20.5
		1-(3-trimethyl silyl phenyl) 2,2,2-trifluoromethyl ethanone hydrate	????21.7

Claims (19)

1. The method of the compound shown in 1 one kinds of manufacturing formulas (I):

   

   R wherein ₁, R ₂, R ₃Be C independently ₁～C ₄Alkyl is characterized in that the following step: a) add the compound shown in 1 equivalent formula (II) in the mixture of an excessive magnesium in a kind of suitable organic solvent:

   

   Wherein X represents Cl, Br or I; R ₁, R ₂And R ₃Define the same; B) add excessive trifluoracetic acid lithium then; C) add a kind of suitable reaction terminating agent then.
2. 2. manufacture method as claimed in claim 1 wherein also is included in the step (a) added a kind of suitable initiator earlier before the compound shown in the adding formula (II) in the mixture of excessive magnesium in suitable organic solvent.
3. 3. manufacture method as claimed in claim 2, wherein suitable initiator are glycol dibromide.
4. 4. manufacture method as claimed in claim 3, wherein R ₁, R ₂And R ₃Each is a methyl.
5. 5. manufacture method as claimed in claim 4, wherein X is Br.
6. 6. manufacture method as claimed in claim 5, wherein the suitable organic solvent in step (a) is a tetrahydrofuran (THF).
7. 7. manufacture method as claimed in claim 6, wherein 1.05 normal magnesium mix with tetrahydrofuran (THF) in step (a).
8. 8. manufacture method as claimed in claim 7 wherein adds 1.1 normal trifluoracetic acid lithiums in step (b).
9. 9. manufacture method as claimed in claim 8, wherein the trifluoracetic acid lithium was wanted to mix with tetrahydrofuran (THF) earlier before adding in step (b).
10. 10. manufacture method as claimed in claim 9, wherein the water content of trifluoracetic acid lithium/tetrahydrofuran solution is less than about 200ppm.
11. 11. manufacture method as claimed in claim 10, wherein suitable reaction terminating agent comprises water/37% hydrochloric acid/Glacial acetic acid/heptane.
12. 12. manufacture method as claimed in claim 11, the weight percent of each component is about 73% water in the wherein suitable reaction terminating agent, 2% hydrochloric acid (37%), 6% Glacial acetic acid and 19% heptane.
13. 13. the method for the compound shown in the purifying formula (I):

    

    R wherein ₁, R ₂, R ₃Be C independently ₁～C ₄Alkyl is characterized in that the following step:

    (a) solution that respectively is the compound shown in 50% the methanol/water mixture washing type (I) in a kind of suitable organic solvent with concentration expressed in percentage by volume.

    (b) be suitable organic solution in 80% and 20% the methanol mixed solution extraction step (a) with the concentration expressed in percentage by volume of first alcohol and water.

    (c) the methanol extraction liquid in the enrichment step (b) to the concentration expressed in percentage by weight of the compound shown in the formula (I) reaches about 13%～18%.

    (d) with the mixture after concentrating in a kind of suitable organic solvent extraction step (c).
14. 14. manufacture method as claimed in claim 13 wherein concentrates the extraction liquid in the step (d).
15. 15. as claim 13 or 14 described manufacture method,

    The preparation process of the compound shown in its Chinese style (I) comprises the following steps:

    (a) in the mixture of an excessive magnesium in a kind of suitable organic solvent, add the compound shown in 1 equivalent formula (II): Wherein X represents Cl, Br or I; R ₁, R ₂And R ₃Define the same;

    (b) add excessive trifluoracetic acid lithium then.

    (c) add a kind of suitable reaction terminating agent then.
16. 16. manufacture method as claimed in claim 15, wherein R ₁, R ₂And R ₃Represent methylidene, X represents Br.
17. 17. manufacture method as claimed in claim 16, wherein the solution of compound in suitable organic solvent shown in step (a) Chinese style (I) is the n-heptane solution of compound shown in the formula (I).
18. 18. manufacture method as claimed in claim 17, the concentration expressed in percentage by weight of compound is 30%～35% shown in the n-heptane solution Chinese style (I) of compound shown in its Chinese style (I).
19. 19. manufacture method as claimed in claim 18, wherein the suitable organic solvent in the step (d) is a heptane.