CN103896757A - Cis-trans isomerization method of 2 or 4-substituted naphthenic acid compound - Google Patents

Abstract

The invention discloses a cis-trans isomerization method of 2 or 4-substituted naphthenic acid compounds. The method comprises the following steps: converting a cis 2 or 4-substituted naphthenic acid compound into a trans 2 or 4-substituted naphthenic acid compound in the presence of a water-containing solvent, and under the conditions of pressure of 0-5 atm, temperature of 120 -200 DEG C and the action of strong alkali. The cis-trans isomerization method provided by the invention not only effectively improves the conversion efficiency of the reaction, has simple treatment and reduces environmental pollution, but also has the advantages of high yield, low cost and short preparation period.

Description

The cis-trans isomerization method of the naphthenic acid compounds of 2 or 4 replacements

Technical field

The present invention relates to a kind of cis-trans isomerization method of naphthenic acid compounds of 2 or 4 replacements.

Background technology

Trans 2 or 4 substituted cyclohexane formic acid IV have industrial use widely, and they are some pharmaceutical prods, the key intermediate of sterilant and some liquid crystal materials.For example, the intermediate (JP6354321) that trans 4-isopropyl hexahydrobenzoic acid is a kind of antidiabetic drug; Anti-form-1,2-cyclohexane diacid is the key intermediate (EP1652848) of novel antipsychotic drug Lurasidone.

In document (JP6354321), once reported that trans 4-isopropyl hexahydrobenzoic acid was transformed from its cis isomerism, but its conversion condition is very harsh, needs high temperature (200 degree) high pressure (200atm), and can only be transformed into 85% and just reached balance.And Japanese has improved above-mentioned condition in patent (US5831118), adopt the KOH aqueous solution and high boiling alkane first to remove water under 160-200 degree condition, form nonhomogeneous system, give like this aftertreatment, particularly suitability for industrialized production is brought very big inconvenience.For all-cis formula 1, the isomerization of 2-cyclohexane cyclohexanedimethanodibasic, American scientist (Siegel, S.; McCaleb, G.S.; Journal of the American Chemical Society, 1959,81,3655-3658) report and adopted 85% phosphoric acid as solvent, be heated to reflux state, reach the object of conversion, but the method also easily reaches inversion equilibrium, be difficult to isomerization complete, finally also need to remove a little cis-isomeride with acetone or ethyl alcohol recrystallization, more fatal is that the method is in actual production, to equipment requirements harshness, be difficult to suitable reactor, so be also not suitable with large-scale industrial production.

In sum, the condition harshness that existing method has, what have is not suitable for scale operation.Therefore, be badly in need of a kind of condition of research and development relatively gentle, be applicable to the cis-trans isomerization method of scale operation.

Summary of the invention

Technical problem to be solved by this invention is, in order to overcome conversion condition harshness in existing cis-trans isomerization method, aftertreatment inconvenience, easily to reach inversion equilibrium, be difficult to isomerization completely, to equipment requirements harshness, the defects such as inapplicable large-scale commercial production, and a kind of cis-trans isomerization method of naphthenic acid compounds of 2 or 4 replacements is provided.Cis-trans isomerization method of the present invention has not only improved reaction transformation efficiency effectively, and aftertreatment is simple, has reduced environmental pollution, and it is high to have yield, and cost is low, the advantage that preparation cycle is short.

The present inventor is through well-designed, and repetition test, finds to utilize with water-containing solvent formation homogeneous system pleasantly surprisedly and can realize this compounds from cis to trans isomerization.

The object of the invention is to, a kind of cis-trans isomerization method of naphthenic acid compounds of 2 or 4 replacements is provided, comprise the following steps: in the solvent that contains water, be that 0atm～5atm, temperature are under the effect of 120 DEG C～200 DEG C and highly basic at pressure, the naphthenic acid of 2 or 4 replacements of cis or its salt be converted into the naphthenic acid salt of trans 2 or 4 replacements.

In the present invention, reactant used can be naphthenic acid or its salt of the naphthenic acid of 2 replacements of cis or its salt, 4 replacements of cis, or is naphthenic acid or its salt of 4 replacements of the naphthenic acid of 2 replacements of the trans mixing of cis or its salt, the trans mixing of cis.The naphthenic acid of 2 replacements of the described trans mixing of cis or its salt, or the naphthenic acid of 4 replacements of the trans mixing of cis or its salt, the quality that refers to cis-compound is greater than 0% and be less than 100% mixture accounting for reactant total mass.The naphthenic acid of 2 replacements of the described trans mixing of cis or its salt, or in the naphthenic acid or its salt of 4 replacements of the trans mixing of cis, preferably trans: the molar ratio of cis is 0.30～1.45.In the naphthenic acid or its salt of 2 replacements of the described trans mixing of cis, preferably trans: the molar ratio of cis is 1.00～1.50.In the naphthenic acid or its salt of 4 replacements of the described trans mixing of cis, preferably trans: the molar ratio of cis is 0.30～0.80.

The group of 2 or 4 described replacements can be the substituting group of this area routine, can be alkyl, haloalkyl or carboxyl.The preferred C of described alkyl₁～C₁₀alkyl, more preferably methyl or sec.-propyl.The preferred trifluoromethyl of described haloalkyl.

The described solvent that contains water can be water, or the mixed solvent of water and alcohol.One or more in described alcohol particular methanol, ethanol, Virahol and ethylene glycol.In described water and the mixed solvent of alcohol, water can mix and carry out described cis-trans isomerization method with arbitrary proportion with alcohol, and general according to the solubleness of reaction substrate, the volume ratio of water and alcohol can be selected to being less than 100% from being greater than 0%.The consumption of the described solvent that contains water can be the reactant of described cis-trans isomerization method is dissolved completely, and the weight ratio of preferred reactant and solvent is 1:3～1:5.In the present invention, described reactant is naphthenic acid or its salt of 2 or 4 replacements of cis.

In the present invention, the naphthenic acid salt of 2 or 4 replacements can be sylvite, sodium salt or lithium salts.

Described highly basic can be the highly basic of this area routine, comprises organic alkali and inorganic strong alkali, preferably inorganic strong alkali.The preferred KOH of described inorganic strong alkali, NaOH or LiOH.

Preferred 1atm～the 5atm of described pressure, more preferably 3atm～5atm.

Preferably 150 DEG C～160 DEG C of described temperature.

Naphthenic acid or its salt of described 2 or 4 replacements of cis, be preferably 1:3～1:10 with the mol ratio of highly basic, more preferably 1:1～1:3.5.

In the present invention, the naphthenic acid salt of trans 2 or 4 replacements that obtain, also can carry out acidifying, to obtain the naphthenic acid of trans 2 or 4 replacements.

Described acidifying can be the acidifying of this area routine, generally carries out acidifying with acid.Described acid is preferably concentrated hydrochloric acid (36%, mass percent).Described acidifying generally makes the pH value of reaction system be adjusted to 1～2.

The reaction process of described cis-trans isomerization method can be monitored with HPLC, generally when the transformation efficiency of reactant reaches 99% terminal that can be reaction when above.

Described cis-trans isomerization method can be carried out in the reactor that can bear 10 kilograms of pressure, as: stainless steel cauldron, toughened glass reactor or enamel reaction still etc.

After described acidifying, also can carry out aftertreatment, to be further purified reaction product.After described acidifying, before aftertreatment, preferably also comprise and washing with water.Described aftertreatment preferably includes the following step: cooling system, filter, and filter cake washes with water, vacuum drying.Described aftertreatment more preferably comprises the following steps: (1) cooling system, filters, and filter cake washes with water, vacuum drying; (2) solid ethanol step (1) being obtained is pulled an oar, and filters, dry.In the step (1) of described aftertreatment, the water yield of washing use is in the preferred 1:1 of weight ratio of product.In the step (2) of described aftertreatment, the amount of the ethanol used of pulling an oar is the 20%-50%(massfraction of the amount of product).Described cooling preferably to 10 of temperature～30 DEG C.

In the present invention, the signal equation of described isomerization method can be as follows:

Wherein, X is generally alkyl, haloalkyl or the carboxyl of 2 or 4 replacements.

Without prejudice to the field on the basis of common sense, 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 be commercially available obtaining all.

Positive progressive effect of the present invention is: cis-trans isomerization method of the present invention, transformation efficiency is high, yield is good, easy handling, the product quality that obtains is stable, purity is high, reduce environmental pollution, reduced raw material consumption, can effectively reduce production cost, and be applicable to carrying out industrial amplification production.

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, according to ordinary method and condition, or selects according to catalogue.

Embodiment 1: trans 1, the preparation of 2-cyclohexane diacid

Take 220 grams, tap water in the stainless steel cauldron of 500mL, add 126 grams of NaOH solids in batches, then add cis 1,70 grams of 2-cyclohexane diacid, sealing, then be heated to 150 degree, the pressure of reaction system reaches 3atm, and at this temperature stirring reaction 72 hours, HPLC follows the tracks of detection, to exceeding 95% to transforming, get final product stopped reaction.Be cooled to room temperature, add 140 grams of tap water, under stirring, add concentrated hydrochloric acid (250 grams), until its pH=1-2 has a large amount of white solids to separate out, be cooled to 25 degree, filter, filter cake 140 grams of water washings of water again, vacuum drying obtains 68 grams of white solids, detect knownly, contain 2% raw material, with the making beating of 50ml ethanol, filter, dry, obtain 65 gram 99.5% trans 1,2-cyclohexane diacid.

Embodiment 2: the preparation of trans 4-methyl-cyclohexyl alkane formic acid

Add 166 grams, tap water in the stainless steel cauldron of 500mL, add 125 grams of KOH solids in batches, then add the 4-methyl-cyclohexyl alkane formic acid mixtures that cis-trans mixes (transly to account for 32%; Cis accounts for 68%, molar percentage) 142 grams, this reaction system is clear liquor, sealing, then be heated to 150 degree, the pressure of reaction system reaches 3atm, and at this temperature stirring reaction 20 hours, HPLC follows the tracks of detection, to exceeding 99% to transformation efficiency, gets final product stopped reaction.Be cooled to room temperature, add the tap water of 140 grams, under stirring, add about 250 grams of dense HCl(), modulation pH=1-2, has a large amount of white solids to separate out, and is cooled to 25 degree, filter, filter cake 140 grams of water washings of water again, vacuum drying obtains 135 grams of pure trans 4-methyl-cyclohexyl alkane formic acid.

Embodiment 3: trans 1, the preparation of 2-cyclohexane diacid

Concrete operations reference example 1, is with the difference of embodiment 1, changes NaOH into KOH, the cis 1 of 410 grams, and 2-cyclohexane diacid obtains 312 grams of pure trans target molecules.

Embodiment 4: trans 1, the preparation of 2-cyclohexane diacid

Concrete operations reference example 1, is with the difference of embodiment 1, the cis-trans of 110 grams mix 1,2-cyclohexane diacid (cis raw material: trans raw material=41:59, mol ratio), makes alkali, 140 degree isomerization 5 hours with KOH.Finally obtain 89 grams of pure trans products.

Embodiment 5: the preparation of trans 4-methyl-cyclohexyl alkane formic acid

Add 60 grams of 120 grams, tap water and ethylene glycol in the stainless steel cauldron of 500mL, add 125 grams of KOH solids in batches, then add the 4-methyl-cyclohexyl alkane formic acid mixtures that cis-trans mixes (transly to account for 32%; Cis accounts for 68%, molecular fraction) 142 grams, this reaction system is clear liquor, sealing, is then heated to 150 degree, and at this temperature stirring reaction 20 hours, HPLC follows the tracks of detection, extremely exceedes 99% to transformation efficiency, gets final product stopped reaction.Be cooled to room temperature, add the tap water of 140 grams, under stirring, add about 250 grams of dense HCl(), modulation pH=1-2, has a large amount of white solids to separate out, and is cooled to 25 degree, filter, filter cake 140 grams of water washings of water again, vacuum drying obtains 135 grams of pure trans 4-methyl-cyclohexyl alkane formic acid.

Embodiment 6: the preparation of trans 4-sec.-propyl-naphthenic acid

Add 166 grams, tap water in the stainless steel cauldron of 500mL, add 125 grams of KOH solids in batches, (trans mol ratio accounts for 27% then to add 150 grams, 4-sec.-propyl-naphthenic acid mixture that cis-trans mixes; Cis accounts for 73%) (this raw material is directly to reduce from 4-isopropyl acid, reference: EP0196222), this reaction system is clear liquor, sealing, then be heated to 150 degree, and at this temperature stirring reaction 20 hours, HPLC follows the tracks of detection, to exceeding 99% to transformation efficiency, get final product stopped reaction.Be cooled to room temperature, add the tap water of 140 grams, under stirring, add about 300 grams of dense HCl(), modulation pH=1-2, has a large amount of white solids to separate out, and is cooled to 25 degree, filter, filter cake 140 grams of water washings of water again, vacuum drying obtains 140 grams of pure trans 4-base isopropyl-naphthenic acids.

Embodiment 7: the preparation of trans 4-normal-butyl-naphthenic acid

Add 100 grams, tap water and 100g ethanol in the stainless steel cauldron of 500mL, add 125 grams of LiOH solids in batches, (trans mol ratio accounts for 42% then to add 150 grams, 4-normal-butyl-naphthenic acid mixture that cis-trans mixes; Cis accounts for 58%) (this raw material is directly to reduce from 4-n-butylbenzene formic acid, reference: EP0196222), this reaction system is clear liquor, sealing, is then heated to 150 degree, (pressure of reaction system reaches 5atm), then stirring reaction 50 hours at this temperature, HPLC follows the tracks of detection, to exceeding 99% to transformation efficiency, gets final product stopped reaction.Be cooled to room temperature, remove part solubility promoter ethanol under reduced pressure, and then add the tap water of 50 grams, under stirring, add about 300 grams of dense HCl(), modulation pH=1-2, has a large amount of white solids to separate out, be cooled to 25 degree, filter, filter cake 100 grams of water washings of water again, vacuum drying obtains 110 grams of pure trans 4-normal-butyl-naphthenic acids.

Embodiment 8: the preparation of trans Isosorbide-5-Nitrae-cyclohexane diacid

Take 220 grams of ethylene glycol in the stainless steel cauldron of 500mL, add 126 grams of KOH solids in batches, then add 70 grams of cis-trans mixture Isosorbide-5-Nitrae-cyclohexane diacid, sealing, then be heated to 150 degree, (pressure of reaction system reaches 5atm), and at this temperature stirring reaction 72 hours, HPLC follows the tracks of detection, to exceeding 95% to transforming, get final product stopped reaction.Be cooled to room temperature, most of ethylene glycol is removed in decompression, then adds 140 grams of tap water, under stirring, add concentrated hydrochloric acid (250 grams), until its pH=1-2 has a large amount of white solids to separate out, be cooled to 25 degree, filter filter cake 140 grams of water washings of water again, vacuum drying obtains 60 grams of white solids, detects knownly, contains 2% raw material,, with the making beating of 50ml ethanol, filter, dry, obtain the trans Isosorbide-5-Nitrae-cyclohexane diacid of 55 gram 99.5%.

Embodiment 9: the preparation of trans 4-trifluoromethyl-naphthenic acid

Add 150 grams, tap water and 15g methyl alcohol in the stainless steel cauldron of 500mL, add 105 grams of LiOH solids in batches, (trans mol ratio accounts for 35% then to add 150 grams, 4-trifluoromethyl-naphthenic acid mixture that cis-trans mixes; Cis accounts for 65%) (along anti-mixing raw material prepare reference: US5831118), this reaction system is clear liquor, sealing, then be heated to 150 degree, (pressure of reaction system reaches 4atm), then stirring reaction 80 hours at this temperature, HPLC follows the tracks of detection, to exceeding 99% to transformation efficiency, get final product stopped reaction.Be cooled to room temperature, remove part solubility promoter methyl alcohol under reduced pressure, and then add the tap water of 50 grams, under stirring, add about 300 grams of dense HCl(), modulation pH=1-2, has a large amount of white solids to separate out, be cooled to 25 degree, filter, filter cake 100 grams of water washings of water again, vacuum drying obtains 110 grams of pure trans 4-trifluoromethyl-naphthenic acids.

Claims (10)

1. the cis-trans isomerization method of the naphthenic acid compounds of 2 or 4 replacements, it is characterized in that comprising the following steps: in the solvent that contains water, be that 0atm～5atm, temperature are under the effect of 120 DEG C～200 DEG C and highly basic at pressure, the naphthenic acid of 2 or 4 replacements of cis or its salt be converted into the naphthenic acid salt of trans 2 or 4 replacements.

2. cis-trans isomerization method as claimed in claim 1, is characterized in that: the naphthenic acid salt of described trans 2 or 4 replacements is sylvite, sodium salt or lithium salts.

3. cis-trans isomerization method as claimed in claim 1, is characterized in that: the group of described replacement is alkyl, haloalkyl or carboxyl; Described alkyl is C₁～C₁₀alkyl, preferable methyl or sec.-propyl; Described haloalkyl is trifluoromethyl.

4. cis-trans isomerization method as claimed in claim 1, is characterized in that: the described solvent that contains water is water, or the mixed solvent of water and alcohol; Described alcohol is one or more in methyl alcohol, ethanol, Virahol and ethylene glycol.

5. cis-trans isomerization method as claimed in claim 1, is characterized in that: described highly basic is inorganic strong alkali; Described inorganic strong alkali is KOH, NaOH or LiOH.

6. cis-trans isomerization method as claimed in claim 1, is characterized in that: described temperature is 150 DEG C～160 DEG C; Described pressure is 1atm～5atm, preferably 3atm～5atm.

7. cis-trans isomerization method as claimed in claim 1, is characterized in that: naphthenic acid or its salt of described 2 or 4 replacements of cis, with the mol ratio of highly basic be 1:3～1:10.

8. cis-trans isomerization method as claimed in claim 1, is characterized in that: in described cis-trans isomerization method, the naphthenic acid salt of trans 2 or 4 replacements that obtain, also carries out acidifying, to obtain the naphthenic acid of trans 2 or 4 replacements.

9. cis-trans isomerization method as claimed in claim 8, is characterized in that: described acidifying makes the pH value of reaction system be adjusted to 1～2.

10. cis-trans isomerization method as claimed in claim 8, is characterized in that: after described acidifying, also carry out aftertreatment, described aftertreatment comprises the following steps: cooling system, filters, and filter cake washes with water, vacuum drying; Described cooling temperature is for being cooled to 10～30 DEG C.