CN105085296B - The method that one kind prepares trans 4 (t-butoxycarbonyl amino) cyclohexanecarboxylic acid intermediate isomerization - Google Patents
The method that one kind prepares trans 4 (t-butoxycarbonyl amino) cyclohexanecarboxylic acid intermediate isomerization Download PDFInfo
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Abstract
The invention discloses the method that one kind prepares trans 4 (t-butoxycarbonyl amino) cyclohexanecarboxylic acid intermediate isomerization, salt process, isomerization, neutralization, postprocessing working procedures are taken into, make the trans 4 cyclohexane-carboxylic acid high purity more than 98% prepared.The present invention has advantages below 1) side reaction is few, and the obtained trans purity of product is high, and transisomer purity is greatly improved to 98% from 25%；2) solvent is made with water, instead of the high boiling solvent of document report, more environmental protection；3) catalysis base amount it is few, can recovery, the solid waste of generation is few, and pollution is few, is adapted to industrialized production.
Description
Technical field
The invention belongs to chemistry or medicinal chemistry art, and in particular to one kind prepares trans -4- (t-butoxycarbonyl amino)
The method of cyclohexanecarboxylic acid intermediate isomerization.
Background technology
4- cyclohexane-carboxylic acids are the key intermediates for preparing trans -4- (t-butoxycarbonyl amino) cyclohexanecarboxylic acid, are
Important medicine intermediate, is mainly used to the class medicines such as synthesis dipeptides, tripeptides, isoquinine cyclic ketones.There are two kinds of alloisomerisms in it
Body：Cis -4- cyclohexane-carboxylic acids and trans-4-amino naphthenic acid, wherein transisomer are more aobvious than cis-isomer
Now more unique activity and characteristic, has drawn attention as medicine intermediate and auxiliary chemicals.
At present, industrial production passes through in suitable made from PABA hydrogenating reduction, trans-4-amino naphthenic acid
Trans content is 20%-25%, if being directly separated, trans product yield it is too low, it is necessary to further isomerization, by cis-isomer
It is converted into transisomer.
The document that Sandor gobolos etc. are delivered《Highly Selective Preparation oftrans-4-
Amino-cyclohexane CarboxylicAcid from cis-Isomer overNickel Catalyst》
In report under 130 DEG C, 100bar pressure, raney ni catalysis be hydrogenated with 5 hours isomerization trans/cis isomer proportions be 7/
3.This method needs autoclave, higher to equipment requirement, and Raney's nickel operating process has spontaneous combustion risk.
Patent TWI280232B is reported in sodium hydroxide, alkanol potassium, by 4- cyclohexanecarboxylic acid's reactive derivatives
Cis-isomer, along back mixing compound, base isomerization is protected by amino if necessary and obtains trans-4-amino hexamethylene carboxylic
The amido protecting derivative and its salt of hydrochlorate, trans-4-amino cyclohexane-carboxylic acid.
Patent US 7314950 is reported first uses paranitrobenzaldehyde or tertiary fourth by cis 4- cyclohexane-carboxylic acids methyl esters
Base sulfonic acid chloride carries out amido protecting, then by sodium methoxide isomerization, last Deprotection obtains trans-4-amino naphthenic acid
Methyl esters.
Two above patent needs first to carry out amido protecting, re-isomerization, last Deprotection, and cumbersome, yield is low.
And use high boiling solvent xylene, naphthalane, mesitylene, cymol etc. in reaction, recovery high energy consumption,
Pollution is big.Metal alkali isomerization is used, substantial amounts of abraum salt is produced, solid waste is difficult.
Therefore, really being able to be applied to that operation in industrial production is succinct efficiently, polluting less, environmental protection, greatly improving
The isomerization method of trans-4-amino naphthenic acid content needs to research and develop.
The content of the invention
It is an object of the invention to overcome it is of the prior art it is not enough there is provided one kind operation it is succinct efficiently, pollute less, green
The method of the high-purity trans-4-amino naphthenic acid of environmental protection.
According to an aspect of the present invention, trans -4- (t-butoxycarbonyl amino) hexamethylene is prepared the invention provides one kind
The method of carboxylic acid intermediates isomerization, comprises the following steps：
1) into salt process：Using water as solvent, in the presence of organic base, a little alkane formic acid mixtures of suitable, trans-4-amino ring
The organic slat solution of a little alkane formic acid of suitable, trans-4-amino ring, the suitable, trans-4-amino are obtained into salt 0.5-1h at 30-40 DEG C
Cis- 4- cyclohexane-carboxylic acids and trans- 4- cyclohexane-carboxylic acids mol ratio are 80~20 in naphthenic acid mixture：20；
Organic base is selected from DMF, triethylamine, triethylene diamine, the carbon -7- alkene of 1,8- diazabicylos 11,1,5- bis-
Azabicyclo [4.3.0] -5- nonenes, 2,4,6- trimethylpyridines, DMAP, pyridine, N-methylmorpholine, tetramethyl
Any of ethylenediamine, cyclohexylamine, organic base amount for suitable, trans-4-amino naphthenic acid mole 0.1~
2.0 again；
2) isomerization process：Step 1) in organic slat solution be transferred in autoclave, add metal nano catalyst,
In 160~210 DEG C, isomerization reaction 17~24 hours is carried out under 0.9~1.8MPa；Catalyst amount is suitable, trans-4-amino
The 0.03-0.05 of naphthenic acid total weight of the mixture；
3) neutralization step：Step 2) after isomerization reaction terminates, it is 6-8 that pH is neutralized to acid in 10-40 DEG C under normal pressure, is obtained
To suitable, the trans-4-amino naphthenic acid aqueous solution, HPLC monitors cis- 4- cyclohexane-carboxylic acids and trans- 4- ammonia in reaction solution
Butylcyclohexanecarboxylic acid mol ratio is 1-10：95, the acid is any of sulfuric acid, phosphoric acid, boric acid, hydrochloric acid, nitric acid；
4) postprocessing working procedures：Step 3) gained pH is warming up to 50 DEG C for the 6-8 aqueous solution, and Isosorbide-5-Nitrae-dioxane is then added dropwise
To solution into muddiness, then the growing the grain aging 0.5h at 50 DEG C is at the uniform velocity cooled to 10 DEG C, and taken out after 10 DEG C of crystallization 3h in 3h
High-purity trans-4-amino naphthenic acid is filtered to obtain, trans-4-amino naphthenic acid purity is more than 98%；
Step 2) described in metal nano catalyst be manganese acetylacetonate and barium hydroxide mixture, particle diameter is 100-
200 nanometers, wherein manganese ion and barium ions mol ratio are 1:3.5, it is prepared from by following preparation method：Manganese acetylacetonate is molten
In the in the mixed solvent of acetone and petroleum ether, backflow is warming up to, 1N baryta water is then added dropwise, after completion of dropwise addition certainly
Room temperature crystallization so is cooled to, ultrasound is opened when solution turned cloudy, maintains suction filtration after ultrasound 3h to obtain particle diameter and be 10-30 microns and urges
Agent, the metal nano catalyst that particle diameter is 100-200 nanometers is crushed to by ball mill.
In nanocatalyst preparation process of the present invention, taking the method for dissolving makes manganese acetylacetonate be mixed with barium hydroxide
It is even, it is ensured that the uniformity of two metal ion species in the nanocatalyst prepared；Start rank in crystal nucleation in Crystallization Process
The method that section takes ultrasound, promotes crystal grain small, finally reaches nano-scale dimension with reference to the method for physical crushing.
It is preferred that, step 1) into salt process, organic base is selected from pyridine, the carbon -7- alkene of 1,8- diazabicylos 11,4- bis-
Any one in methylamino pyridine；
It is preferred that, step 3) in neutralization step acid in phosphoric acid, hydrochloric acid, sulfuric acid any one.
It is preferred that, step 1) into salt process, organic base amount is suitable, trans-4-amino naphthenic acid mole
1.0~2.0 times.
The beneficial effects of the present invention are：
1st, the invention provides one kind with water as solvent, under organic base catalytic effect, high-temperature pressurizing, suitable, trans -4- ammonia
The method of Butylcyclohexanecarboxylic acid isomerization, side reaction is few, and the obtained trans purity of product is high, and transisomer purity is big from 25%
Width is improved to 98%.
2nd, solvent is made with water, instead of the high boiling solvent of document report, more environmental protection.
3rd, catalysis base amount it is few, can recovery, the solid waste of generation is few, and pollution is few, is adapted to industrialized production.
Embodiment
Following that the present invention is described in detail by specific embodiment, following examples are used to explain the present invention, and
It is not limitation of the present invention.
Embodiment 1
Add that 143.2g is suitable into reaction bulb, trans-4-amino naphthenic acid (wherein transisomer and syn-isomerism
Body is 1：1), 8 times of suitable, trans-4-amino naphthenic acid volume ratio water, 2.0 times of suitable, trans-4-amino naphthenic acids
The pyridine of mole, 30 DEG C a little alkane formic acid of suitable, trans-4-amino ring are obtained into salt 0.5h organic slat solution；
Above-mentioned organic slat solution is transferred in 2L autoclaves, suitable, trans-4-amino naphthenic acid mixture is added total
The metal nano catalyst of weight 0.03, in 160 DEG C, carries out isomerization reaction 17 hours under 0.9MPa；
After isomerization reaction terminates, it is 6 that pH is neutralized to sulfuric acid in 10 DEG C under normal pressure, obtains suitable, trans-4-amino hexamethylene
Cis- 4- cyclohexane-carboxylic acids are with trans- 4- cyclohexane-carboxylic acids mol ratio in alkane aqueous formic acid, HPLC monitoring reaction solutions
10：95；The aqueous solution is warming up to 50 DEG C, and Isosorbide-5-Nitrae-dioxane is then added dropwise to solution into muddiness, the growing the grain aging 0.5h at 50 DEG C,
Then 10 DEG C are at the uniform velocity cooled in 3h, and suction filtration obtains high-purity trans-4-amino naphthenic acid after 10 DEG C of crystallization 3h, instead
Formula -4- cyclohexane-carboxylic acids purity is 98.5%, yield 80%.
The metal nano catalyst is the mixture of manganese acetylacetonate and barium hydroxide, and particle diameter is 100-200 nanometers, its
Middle manganese ion is 1 with barium ions mol ratio:3.5, it is prepared from by following preparation method：Manganese acetylacetonate is dissolved in acetone and stone
The in the mixed solvent of oily ether, is warming up to backflow, and 1N baryta water is then added dropwise, room is naturally cooled to after completion of dropwise addition
Warm crystallization, opens ultrasound when solution turned cloudy, maintains suction filtration after ultrasound 3h to obtain the catalyst that particle diameter is 10-30 microns, by
Ball mill is crushed to the metal nano catalyst that particle diameter is 100-200 nanometers.
Embodiment 2
Add that 143.2g is suitable into reaction bulb, trans-4-amino naphthenic acid (wherein transisomer and syn-isomerism
Body is 1：2), 8 times of suitable, trans-4-amino naphthenic acid volume ratio water, 1.5 times of suitable, trans-4-amino naphthenic acids
Carbon -7- the alkene of 1,8- diazabicylos 11 of mole, 40 DEG C obtain the organic of a little alkane formic acid of suitable, trans-4-amino ring into salt 1h
Salting liquid；
Above-mentioned organic slat solution is transferred in 2L autoclaves, suitable, trans-4-amino naphthenic acid mixture is added total
The metal nano catalyst of weight 0.05, in 210 DEG C, carries out isomerization reaction 24 hours under 1.8MPa；
After isomerization reaction terminates, it is 7 that pH is neutralized to phosphoric acid in 20 DEG C under normal pressure, obtains suitable, trans-4-amino hexamethylene
Cis- 4- cyclohexane-carboxylic acids are with trans- 4- cyclohexane-carboxylic acids mol ratio in alkane aqueous formic acid, HPLC monitoring reaction solutions
8：95；The aqueous solution is warming up to 50 DEG C, and Isosorbide-5-Nitrae-dioxane is then added dropwise to solution into muddiness, the growing the grain aging 0.5h at 50 DEG C,
Then 10 DEG C are at the uniform velocity cooled in 3h, and suction filtration obtains high-purity trans-4-amino naphthenic acid after 10 DEG C of crystallization 3h, instead
Formula -4- cyclohexane-carboxylic acids purity is 98.6%, yield 82%.
Metal nano method for preparing catalyst be the same as Example 1.
Embodiment 3
Add that 143.2g is suitable into reaction bulb, trans-4-amino naphthenic acid (wherein transisomer and syn-isomerism
Body is 1：3), 8 times of suitable, trans-4-amino naphthenic acid volume ratio water, 1.5 times of suitable, trans-4-amino naphthenic acids
The DMAP of mole, 40 DEG C a little alkane formic acid of suitable, trans-4-amino ring are obtained into salt 1h organic slat solution；
Above-mentioned organic slat solution is transferred in 2L autoclaves, suitable, trans-4-amino naphthenic acid mixture is added total
The metal nano catalyst of weight 0.04, in 160 DEG C, carries out isomerization reaction 20 hours under 1.3MPa；
After isomerization reaction terminates, it is 6 to be neutralized with hydrochloric acid under normal pressure in 30 DEG C to pH, obtains suitable, trans-4-amino hexamethylene
Cis- 4- cyclohexane-carboxylic acids are with trans- 4- cyclohexane-carboxylic acids mol ratio in alkane aqueous formic acid, HPLC monitoring reaction solutions
5：95；Obtained aqueous solution is warming up to 50 DEG C, Isosorbide-5-Nitrae-dioxane is then added dropwise to solution into muddiness, the growing the grain aging at 50 DEG C
0.5h, is then at the uniform velocity cooled to 10 DEG C in 3h, and suction filtration obtains high-purity trans-4-amino hexamethylene first after 10 DEG C of crystallization 3h
Acid, trans-4-amino naphthenic acid purity 98%, yield 78%.
Metal nano method for preparing catalyst be the same as Example 1.
Embodiment 4
Add that 143.2g is suitable into reaction bulb, trans-4-amino naphthenic acid (wherein transisomer and syn-isomerism
Body is 1：4), 8 times of suitable, trans-4-amino naphthenic acid volume ratio water, 1.0 times of suitable, trans-4-amino naphthenic acids
The DMAP of mole, 30 DEG C into salt 0.5 a little alkane formic acid of suitable, trans-4-amino ring organic slat solution；
Above-mentioned organic slat solution is transferred in 2L autoclaves, suitable, trans-4-amino naphthenic acid mixture is added total
The metal nano catalyst of weight 0.04, in 180 DEG C, carries out isomerization reaction 20 hours under 1.0MPa；
After isomerization reaction terminates, it is 6 that pH is neutralized to nitric acid in 20 DEG C under normal pressure, obtains suitable, trans-4-amino hexamethylene
Cis- 4- cyclohexane-carboxylic acids are with trans- 4- cyclohexane-carboxylic acids mol ratio in alkane aqueous formic acid, HPLC monitoring reaction solutions
3：95；Obtained aqueous solution is warming up to 50 DEG C, Isosorbide-5-Nitrae-dioxane is then added dropwise to solution into muddiness, the growing the grain aging at 50 DEG C
0.5h, is then at the uniform velocity cooled to 10 DEG C in 3h, and suction filtration obtains high-purity trans-4-amino hexamethylene first after 10 DEG C of crystallization 3h
Acid, trans-4-amino naphthenic acid purity is 98.5%, yield 81%.
Metal nano method for preparing catalyst be the same as Example 1.
Embodiment 5
Add that 143.2g is suitable into reaction bulb, trans-4-amino naphthenic acid (wherein transisomer and syn-isomerism
Body is 1：4), 8 times of suitable, trans-4-amino naphthenic acid volume ratio water, 1.3 times of suitable, trans-4-amino naphthenic acids
The pyridine of mole, 30-40 DEG C a little alkane formic acid of suitable, trans-4-amino ring are obtained into salt 0.5-1h organic slat solution；
Above-mentioned organic slat solution is transferred in 2L autoclaves, suitable, trans-4-amino naphthenic acid mixture is added total
The metal nano catalyst of weight 0.03, in 160 DEG C, carries out isomerization reaction 24 hours under 0.9MPa；
After isomerization reaction terminates, it is 7 that pH is neutralized to boric acid in 30 DEG C under normal pressure, obtains suitable, trans-4-amino hexamethylene
Cis- 4- cyclohexane-carboxylic acids are with trans- 4- cyclohexane-carboxylic acids mol ratio in alkane aqueous formic acid, HPLC monitoring reaction solutions
5：95；Obtained aqueous solution is warming up to 50 DEG C, Isosorbide-5-Nitrae-dioxane is then added dropwise to solution into muddiness, the growing the grain aging at 50 DEG C
0.5h, is then at the uniform velocity cooled to 10 DEG C in 3h, and suction filtration obtains high-purity trans-4-amino hexamethylene first after 10 DEG C of crystallization 3h
Acid, trans-4-amino naphthenic acid purity is 98%, yield 75%.
Metal nano method for preparing catalyst be the same as Example 1.
The invention is not restricted to above-described embodiment, any letter that all technical spirits according to the present invention are made to above-described embodiment
Single, equivalent variations or modification, are belonged in the range of the technology of the present invention.
Claims (3)
1. a kind of method of trans -4- (t-butoxycarbonyl amino) cyclohexanecarboxylic acid intermediate isomerization, comprises the following steps：
1) into salt process：Using water as solvent, in the presence of organic base, suitable, trans-4-amino naphthenic acid mixture exists
30-40 DEG C suitable trans-4-amino naphthenic acid is obtained into salt 0.5-1h organic slat solution, suitable, the trans-4-amino ring
Cis- 4- cyclohexane-carboxylic acids and trans- 4- cyclohexane-carboxylic acids mol ratio are 80~20 in hexane formic acid mixtures：20；Have
Machine alkali is selected from DMF, triethylamine, triethylene diamine, the carbon -7- alkene of 1,8- diazabicylos 11,1,5- phenodiazines
Miscellaneous bicyclic [4.3.0] -5- nonenes, 2,4,6- trimethylpyridines, DMAP, pyridine, N-methylmorpholine, tetramethyl second
Any of diamines, cyclohexylamine, organic base amount are the 1.0~2.0 of suitable, trans-4-amino naphthenic acid mole
Times；
2) isomerization process：Step 1) in organic slat solution be transferred in autoclave, add metal nano catalyst, in
160~210 DEG C, isomerization reaction 17~24 hours is carried out under 0.9~1.8MPa；Metal nano catalyst amount for it is suitable, trans-
The 0.03-0.05 of 4- cyclohexane-carboxylic acid total weight of the mixture；
3) neutralization step：Step 2) after isomerization reaction terminates, it is 6-8 that pH is neutralized to acid in 10-40 DEG C under normal pressure, is obtained
Cis- 4- cyclohexane-carboxylic acids and trans- 4- amino in suitable, the trans-4-amino naphthenic acid aqueous solution, HPLC monitoring reaction solutions
Naphthenic acid mol ratio is 1-10：95, the acid is any of sulfuric acid, phosphoric acid, boric acid, hydrochloric acid, nitric acid；
4) postprocessing working procedures：Step 3) gained pH is warming up to 50 DEG C for the 6-8 aqueous solution, and Isosorbide-5-Nitrae-dioxane is then added dropwise to molten
Liquid is into muddiness, the growing the grain aging 0.5h at 50 DEG C, and 10 DEG C are then at the uniform velocity cooled in 3h, and suction filtration is obtained after 10 DEG C of crystallization 3h
High-purity trans-4-amino naphthenic acid, trans-4-amino naphthenic acid purity is more than 98%；
Step 2) described in metal nano catalyst be manganese acetylacetonate and barium hydroxide mixture, particle diameter receives for 100-200
Rice, wherein manganese ion are 1 with barium ions mol ratio:3.5, it is prepared from by following preparation method：Manganese acetylacetonate is dissolved in third
The in the mixed solvent of ketone and petroleum ether, is warming up to backflow, and 1N baryta water is then added dropwise, natural after completion of dropwise addition
Room temperature crystallization is cooled to, ultrasound is opened when solution turned cloudy, maintains suction filtration after ultrasound 3h to obtain the catalysis that particle diameter is 10-30 microns
Agent, the metal nano catalyst that particle diameter is 100-200 nanometers is crushed to by ball mill.
2. the side of the trans -4- of one kind (t-butoxycarbonyl amino) cyclohexanecarboxylic acid intermediate isomerization according to claim 1
Method, it is characterised in that：Step 1) into salt process, organic base is selected from pyridine, the carbon -7- alkene of 1,8- diazabicylos 11,4- bis-
Methylamino pyridine.
3. the side of the trans -4- of one kind (t-butoxycarbonyl amino) cyclohexanecarboxylic acid intermediate isomerization according to claim 1
Method, it is characterised in that：Step 3) in neutralization step acid in phosphoric acid, hydrochloric acid, sulfuric acid any one.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200400165A (en) * | 2002-03-18 | 2004-01-01 | Tanabe Seiyaku Co | Process for preparing trans-4-aminocylcohexanecarboxylic acids |
| JP2010006752A (en) * | 2008-06-27 | 2010-01-14 | Asahi Kasei Chemicals Corp | Method for separating cis/trans-isomer mixture of 4-aminocyclohexane-1-carboxylic acid |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5831118A (en) * | 1996-06-18 | 1998-11-03 | Katayama Seiyakusyo Co., Ltd. | Epimerization of 2- or 4- substituted cyclohexanecarboxylic acids |
| DE60333733D1 (en) * | 2002-03-12 | 2010-09-23 | Shinonogi & Co Ltd | Clohexancarbonsäurederivats |
| CN103896757B (en) * | 2012-12-24 | 2016-05-11 | 上海彩迩文生化科技有限公司 | The cis-trans isomerization method of the naphthenic acid compounds of 2 or 4 replacements |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200400165A (en) * | 2002-03-18 | 2004-01-01 | Tanabe Seiyaku Co | Process for preparing trans-4-aminocylcohexanecarboxylic acids |
| JP2010006752A (en) * | 2008-06-27 | 2010-01-14 | Asahi Kasei Chemicals Corp | Method for separating cis/trans-isomer mixture of 4-aminocyclohexane-1-carboxylic acid |
Non-Patent Citations (1)
| Title |
|---|
| 4-Dimethylaminodi(2-thienyl)cyclohexylcarbinol and Related Compounds;Frank J. Villani, et al.;《j. org. chem.》;19640930;第29卷;2585-2587 * |
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