CN102911066B - Synthesis method of trans-4-amino cyclohexanecarboxylic acid derivative - Google Patents
Synthesis method of trans-4-amino cyclohexanecarboxylic acid derivative Download PDFInfo
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Abstract
The invention relates to a synthesis method of a trans-4-amino cyclohexanecarboxylic acid derivative. The method comprises the following steps of: (1) dissolving 4-carbonyl cyclohexyl ethyl formate in tetrahydrofuran, dropwise adding tetrahydrofuran solution of lithium tri-sec-butylborohydride, aqueous solution of NaOH and hydrogen peroxide in sequence, performing ethyl acetate extraction, washing an organic layer, then separating liquid and concentrating the organic layer to obtain P1; (2) dissolving the P1 in methylene dichloride, adding triethylamine, methanesulfonyl chloride, water and hydrochloric acid aqueous solution in sequence, uniformly stirring and then separating organic phase, and washing, drying and concentrating the organic phase in sequence to obtain P2; (3) dissolving the P2 in dimethyl formamide, adding sodium azide and water in sequence, performing ethyl acetate extraction, and washing, drying and concentrating the organic layer in sequence to obtain P3; and (4) dissolving the P3 in ethanol, adding palladium carbon, hydrogenating at room temperature, keeping overnight, finally filtering off palladium carbon Pd/C, and performing decompression and concentration to obtain oily trans-4-amino cyclohexyl ethyl formate. The synthesis method has the advantages of concise line, low cost, readily available raw material and high safety.
Description
Technical field
The present invention relates to a kind of synthetic method of medicine intermediate product, relate in particular to the synthetic method of trans-4-amino hexahydrobenzoic acid derivative.
Background technology
Medicine intermediate products production integrates the subjects such as organic chemical industry, fine chemistry industry, biology, material, computer, machinery, optics and accurate detection, is comprehensive multi-disciplinary systems engineering.So, the production development of medicine intermediate product, the developmental level that has not only reflected a national Fine Chemical Industry, and reflected to a certain extent a national chemical pharmaceutical industry developmental level, therefore, accelerate medicine intermediate products production, for promoting that a national chemical and medicine industry industry development has vital role.
The amino heptanaphthenic acid of 4-(ACCA) is important medicine intermediate, is mainly used to the class medicines such as synthetic two skins, three skins, pitayine cyclic ketones.There are two kinds of vertical isomer in it: the amino heptanaphthenic acid of cis-4-and trans-4-amino heptanaphthenic acid, wherein trans body manifests more unique activity and characteristic than cis body, as medicine intermediate and auxiliary chemicals, draws attention.
Trans-4-amino hexahydrobenzoic acid, English by name: Ethyl trans-4-aminocyclohexanecarboxylate, molecular formula C
9h
17no
2, molecular weight 171.24, structural formula
, CAS accession number 1678-68-8.Outward appearance is oily matter, has off-odor.Fusing point-46 ℃, 170 ℃ of boiling points, relative density 1.20 ~ 1.218(20/4 ℃), specific refractory power 1.526 ~ 1.513,68 ℃ of flash-points, are insoluble in water, dissolve in ethanol, ethers.Need airtight placement, in air, deposit, polymerization easily occurs.
Trans-4-amino hexahydrobenzoic acid derivative has many biological activitys, and current synthetic route is as shown in following chemical equation:
Owing to all needing to use expensive noble metal catalyst catalysis aromatic ring to cyclohexane ring in above document, cannot reduce costs, also need to use reaction under high pressure, there is certain danger.
Summary of the invention
Technical problem to be solved by this invention is to provide the synthetic method of the trans-4-amino hexahydrobenzoic acid derivative that a kind of route is succinct, with low cost, security is good.
For addressing the above problem, the synthetic method of trans-4-amino hexahydrobenzoic acid derivative of the present invention, comprises the following steps:
(1) 4-carbonyl cyclohexyl ethyl formate is dissolved in tetrahydrofuran (THF) by feed liquid mass volume ratio 1:15 ~ 45, be cooled to-80 ℃, drip the tetrahydrofuran solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride, maintain the temperature at-80 ~-70 ℃, within 2 hours, add, be incubated half an hour; Then the aqueous solution that drips mass concentration and be 8% NaOH, keeps temperature-80 ~-70 ℃, and add half an hour, and the hydrogen peroxide that to drip mass concentration be 30%, keeps temperature-80 ~-70 ℃, within 2 hours, adds; Secondly, naturally be warming up to 0 degree, add ethyl acetate extraction, extraction times 2 times, merges organic layer, with the sodium sulfite aqueous solution that mass concentration is 10%, washs this organic layer non-oxidative, after last separatory, to described organic layer by dried over sodium sulfate to constant weight, concentrated obtain faint yellow oily matter cis-4-hydroxy-cyclohexyl ethyl formate, be denoted as P1; Wherein
The feed liquid mass volume ratio of the tetrahydrofuran solution of described 4-carbonyl cyclohexyl ethyl formate and described 1mol/L 3-sec-butyl lithium borohydride L-selectride is 1:7 ~ 9; The feed liquid mass volume ratio of the aqueous solution of described 4-carbonyl cyclohexyl ethyl formate and described NaOH is 1:8 ~ 10; The feed liquid mass volume ratio of described 4-carbonyl cyclohexyl ethyl formate and described hydrogen peroxide is 1:5 ~ 8; The feed liquid mass volume ratio of described 4-carbonyl cyclohexyl ethyl formate and described ethyl acetate is 1:8 ~ 12; The volume ratio of described organic layer and described sodium sulfite aqueous solution is 1:0.05 ~ 0.2;
(2) described P1 is dissolved in methylene dichloride by feed liquid mass volume ratio 1:10 ~ 20, add triethylamine, and be cooled to-10 ℃, then drip methane sulfonyl chloride, keep temperature-10 ~ 0 ℃, within 1 hour, add, then stir 1 hour, by 5% ~ 15% of the quality of former methane sulfonyl chloride, add methane sulfonyl chloride again at 0 ℃; After half an hour, add successively water, 1mol/L aqueous hydrochloric acid, after stirring, separate organic phase; The NaCl solution washing that last described organic phase is 23% through mass concentration successively, dried over sodium sulfate, to constant weight, concentrate and obtain yellow oil cis 4-mesyloxy cyclohexyl ethyl formate, are denoted as P2; Wherein
The mass ratio of described P1 and described triethylamine is 1:1 ~ 2; The mass ratio of described P1 and described methane sulfonyl chloride is 1:0.60 ~ 1.0; The feed liquid mass volume ratio of described P1 and described water is 1:10 ~ 15; The feed liquid mass volume ratio of described P1 and described aqueous hydrochloric acid is 1:5 ~ 8;
(3) described P2 is dissolved in dimethyl formamide by feed liquid mass volume ratio 1:10 ~ 15, adds sodium azide, and be warming up to 70 ℃, stirring is spent the night; Then add water, and be extracted with ethyl acetate, extraction times 3 times, merges organic layer; This organic layer is with after the water washing of 0.05 ~ 0.2 times of its quality 2 times, through dried over sodium sulfate to constant weight, concentrated obtain red oil trans-4-azido-hexahydrobenzoic acid, be denoted as P3; Wherein
The mass ratio of described P2 and described sodium azide is 1:0.8 ~ 1.2; The feed liquid mass volume ratio of described P2 and described water is 1:8 ~ 12; The feed liquid mass volume ratio of described P2 and described ethyl acetate is 1:8 ~ 12;
(4) described P3 is dissolved in ethanol by feed liquid mass volume ratio 1:8 ~ 12, then adding palladium mass content is 10% palladium carbon Pd/C, under the condition that is 1.0MPa at hydrogen pressure, room temperature hydrogenation is spent the night, finally filter out palladium carbon Pd/C, obtain filtrate, through concentrating under reduced pressure, obtain oily matter trans-4-amino cyclohexyl ethyl formate, be denoted as P4; The mass ratio of wherein said P3 and described palladium carbon Pd/C is 1:0.05 ~ 0.2.
The present invention compared with prior art has the following advantages:
The present invention uses business-like raw material 4-carbonyl cyclohexyl ethyl formate, with L-selectride, carry out selective reduction and become cis-4-hydroxy-cyclohexyl ethyl formate, after becoming methanesulfonates, with sodiumazide, carry out SN2 substitution reaction, rear catalytic reduction obtains the trans 4-aminocyclohexyl ethyl formate needing.This route has been avoided using expensive catalyzer and reaction under high pressure effectively, and route is succinct, with low cost, security good, raw material is easy to get.
Embodiment
embodiment 1the synthetic method of trans-4-amino hexahydrobenzoic acid derivative, comprises the following steps:
By 4-carbonyl cyclohexyl ethyl formate (SM) by feed liquid mass volume ratio 1:35(g/L) be dissolved in tetrahydrofuran (THF) (THF), be cooled to-80 ℃, drip tetrahydrofuran (THF) (THF) solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride, maintain the temperature at-80 ~-70 ℃, within 2 hours, add, be incubated half an hour; Then the aqueous solution that drips mass concentration and be 8% NaOH, keeps temperature-80 ~-70 ℃, and add half an hour, and the hydrogen peroxide that to drip mass concentration be 30%, keeps temperature-80 ~-70 ℃, within 2 hours, adds; Secondly, naturally be warming up to 0 ℃, add ethyl acetate extraction, extraction times 2 times, merges organic layer, with the sodium sulfite aqueous solution that mass concentration is 10%, washs this organic layer, after last separatory, to organic layer by dried over sodium sulfate to constant weight, obtain faint yellow oily matter cis-4-hydroxy-cyclohexyl ethyl formate, be denoted as P1.Wherein
4-carbonyl cyclohexyl ethyl formate (SM) is 1:8.7(g/L with the feed liquid mass volume ratio of tetrahydrofuran (THF) (THF) solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:8.8(g/L with the feed liquid mass volume ratio of the aqueous solution of NaOH); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:6.4(g/L with the feed liquid mass volume ratio of hydrogen peroxide); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:10(g/L with the feed liquid mass volume ratio of ethyl acetate); The volume ratio of organic layer and sodium sulfite aqueous solution is 1:0.1(L/L).
By P1 by feed liquid mass volume ratio 1:15(g/L) be dissolved in methylene dichloride (DCM), add triethylamine (Et3N), and be cooled to-10 ℃, then drip methane sulfonyl chloride (MsCl), keep temperature-10 ~ 0 ℃, within 1 hour, add, then stir 1 hour, by 10% of the quality of former methane sulfonyl chloride (MsCl), add methane sulfonyl chloride (MsCl) again at 0 ℃; After half an hour, add successively water, 1mol/L aqueous hydrochloric acid, after stirring, isolate organic phase; The NaCl solution washing that is 23% finally by mass concentration, dried over sodium sulfate, to constant weight, obtain yellow oil cis 4-mesyloxy cyclohexyl ethyl formate, are denoted as P2.Wherein
The mass ratio of described P1 and described triethylamine is 1:1.76; The mass ratio of described P1 and described methane sulfonyl chloride is 1:0.80; The feed liquid mass volume ratio of described P1 and described water is 1:12.2; The feed liquid mass volume ratio of described P1 and described aqueous hydrochloric acid is 1:6.1.
By P2 by feed liquid mass volume ratio 1:11(g/L) be dissolved in dimethyl formamide (DMF), add sodium azide (NaN3), and be warming up to 70 ℃, stirring is spent the night; Then add water, and be extracted with ethyl acetate, extraction times 3 times, merges organic layer; This organic layer is with after the water washing of 0.1 times of its quality 2 times, through dried over sodium sulfate to constant weight, obtain red oil trans-4-azido-hexahydrobenzoic acid, be denoted as P3.Wherein
The mass ratio of P2 and sodium azide (NaN3) is 1:1.05(g/g); The feed liquid mass volume ratio of P2 and water is 1:10.5(g/L); The feed liquid mass volume ratio of P2 and ethyl acetate is 1:10(g/L).
By P3 by feed liquid mass volume ratio 1:10(g/L) be dissolved in ethanol (EtOH), then adding palladium mass content is 10% palladium carbon, under the condition that is 1.0MPa at hydrogen pressure, room temperature hydrogenation is spent the night, finally filter out palladium carbon, obtain filtrate, concentrating under reduced pressure obtains oily matter 4-aminocyclohexyl ethyl formate, is denoted as P4.Wherein the mass ratio of P3 and palladium carbon Pd/C is 1:0.15(g/g).
embodiment 2the synthetic method of trans-4-amino hexahydrobenzoic acid derivative, comprises the following steps:
By 4-carbonyl cyclohexyl ethyl formate (SM) by feed liquid mass volume ratio 1:15(g/L) be dissolved in tetrahydrofuran (THF) (THF), be cooled to-80 ℃, drip tetrahydrofuran (THF) (THF) solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride, maintain the temperature at-80 ~-70 ℃, within 2 hours, add, be incubated half an hour; Then the aqueous solution that drips mass concentration and be 8% NaOH, keeps temperature-80 ~-70 ℃, and add half an hour, and the hydrogen peroxide that to drip mass concentration be 30%, keeps temperature-80 ~-70 ℃, within 2 hours, adds; Secondly, naturally be warming up to 0 ℃, add ethyl acetate extraction, extraction times 2 times, merges organic layer, with the sodium sulfite aqueous solution that mass concentration is 10%, washs this organic layer, after last separatory, to organic layer by dried over sodium sulfate to constant weight, obtain faint yellow oily matter cis-4-hydroxy-cyclohexyl ethyl formate, be denoted as P1.Wherein
4-carbonyl cyclohexyl ethyl formate (SM) is 1:7(g/L with the feed liquid mass volume ratio of tetrahydrofuran (THF) (THF) solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:8(g/L with the feed liquid mass volume ratio of the aqueous solution of NaOH); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:5(g/L with the feed liquid mass volume ratio of hydrogen peroxide); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:8(g/L with the feed liquid mass volume ratio of ethyl acetate); The volume ratio of organic layer and sodium sulfite aqueous solution is 1:0.05(L/L).
By P1 by feed liquid mass volume ratio 1:10(g/L) be dissolved in methylene dichloride (DCM), add triethylamine (Et3N), and be cooled to-10 ℃, then drip methane sulfonyl chloride (MsCl), keep temperature-10 ~ 0 ℃, within 1 hour, add, then stir 1 hour, by 5% of the quality of former methane sulfonyl chloride (MsCl), add methane sulfonyl chloride (MsCl) again at 0 ℃; After half an hour, add successively water, 1mol/L aqueous hydrochloric acid, after stirring, isolate organic phase; The NaCl solution washing that is 23% finally by mass concentration, dried over sodium sulfate, to constant weight, obtain yellow oil cis 4-mesyloxy cyclohexyl ethyl formate, are denoted as P2.Wherein
The mass ratio of described P1 and described triethylamine is 1:1; The mass ratio of described P1 and described methane sulfonyl chloride is 1:0.6; The feed liquid mass volume ratio of described P1 and described water is 1:10; The feed liquid mass volume ratio of described P1 and described aqueous hydrochloric acid is 1:5.
By P2 by feed liquid mass volume ratio 1:10(g/L) be dissolved in dimethyl formamide (DMF), add sodium azide (NaN3), and be warming up to 70 ℃, stirring is spent the night; Then add water, and be extracted with ethyl acetate, extraction times 3 times, merges organic layer; This organic layer is with after the water washing of 0.05 times of its quality 2 times, through dried over sodium sulfate to constant weight, obtain red oil trans-4-azido-hexahydrobenzoic acid, be denoted as P3.Wherein
The mass ratio of P2 and sodium azide (NaN3) is 1:0.8(g/g); The feed liquid mass volume ratio of P2 and water is 1:8(g/L); The feed liquid mass volume ratio of P2 and ethyl acetate is 1:8(g/L).
By P3 by feed liquid mass volume ratio 1:8(g/L) be dissolved in ethanol (EtOH), then adding palladium mass content is 10% palladium carbon, under the condition that is 1.0MPa at hydrogen pressure, room temperature hydrogenation is spent the night, finally filter out palladium carbon, obtain filtrate, concentrating under reduced pressure obtains oily matter 4-aminocyclohexyl ethyl formate, is denoted as P4.Wherein the mass ratio of P3 and palladium carbon is 1:0.05(g/g).
embodiment 3the synthetic method of trans-4-amino hexahydrobenzoic acid derivative, comprises the following steps:
By 4-carbonyl cyclohexyl ethyl formate (SM) by feed liquid mass volume ratio 1:45(g/L) be dissolved in tetrahydrofuran (THF) (THF), be cooled to-80 ℃, drip tetrahydrofuran (THF) (THF) solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride, maintain the temperature at-80 ~-70 ℃, within 2 hours, add, be incubated half an hour; Then the aqueous solution that drips mass concentration and be 8% NaOH, keeps temperature-80 ~-70 ℃, and add half an hour, and the hydrogen peroxide that to drip mass concentration be 30%, keeps temperature-80 ~-70 ℃, within 2 hours, adds; Secondly, naturally be warming up to 0 ℃, add ethyl acetate extraction, extraction times 2 times, merges organic layer, with the sodium sulfite aqueous solution that mass concentration is 10%, washs this organic layer, after last separatory, to organic layer by dried over sodium sulfate to constant weight, obtain faint yellow oily matter cis-4-hydroxy-cyclohexyl ethyl formate, be denoted as P1.Wherein
4-carbonyl cyclohexyl ethyl formate (SM) is 1:9(g/L with the feed liquid mass volume ratio of tetrahydrofuran (THF) (THF) solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:10(g/L with the feed liquid mass volume ratio of the aqueous solution of NaOH); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:8(g/L with the feed liquid mass volume ratio of hydrogen peroxide); 4-carbonyl cyclohexyl ethyl formate (SM) is 1:12(g/L with the feed liquid mass volume ratio of ethyl acetate); The volume ratio of organic layer and sodium sulfite aqueous solution is 1:0.2(L/L).
By P1 by feed liquid mass volume ratio 1:20(g/L) be dissolved in methylene dichloride (DCM), add triethylamine (Et3N), and be cooled to-10 ℃, then drip methane sulfonyl chloride (MsCl), keep temperature-10 ~ 0 ℃, within 1 hour, add, then stir 1 hour, by 15% of the quality of former methane sulfonyl chloride (MsCl), add methane sulfonyl chloride (MsCl) again at 0 ℃; After half an hour, add successively water, 1mol/L aqueous hydrochloric acid, after stirring, isolate organic phase; The NaCl solution washing that is 23% finally by mass concentration, dried over sodium sulfate, to constant weight, obtain yellow oil cis 4-mesyloxy cyclohexyl ethyl formate, are denoted as P2.Wherein
The mass ratio of described P1 and described triethylamine is 1:2; The mass ratio of described P1 and described methane sulfonyl chloride is 1:1.0; The feed liquid mass volume ratio of described P1 and described water is 1:15; The feed liquid mass volume ratio of described P1 and described aqueous hydrochloric acid is 1:8.
By P2 by feed liquid mass volume ratio 1:15(g/L) be dissolved in dimethyl formamide (DMF), add sodium azide (NaN3), and be warming up to 70 ℃, stirring is spent the night; Then add water, and be extracted with ethyl acetate, extraction times 3 times, merges organic layer; This organic layer is with after the water washing of 0.2 times of its quality 2 times, through dried over sodium sulfate to constant weight, obtain red oil trans-4-azido-hexahydrobenzoic acid, be denoted as P3.Wherein
The mass ratio of P2 and sodium azide (NaN3) is 1:1.2(g/g); The feed liquid mass volume ratio of P2 and water is 1:12(g/L); The feed liquid mass volume ratio of P2 and ethyl acetate is 1:12(g/L).
By P3 by feed liquid mass volume ratio 1:12(g/L) be dissolved in ethanol (EtOH), then adding palladium mass content is 10% palladium carbon, under the condition that is 1.0MPa at hydrogen pressure, room temperature hydrogenation is spent the night, finally filter out palladium carbon, obtain filtrate, concentrating under reduced pressure obtains oily matter 4-aminocyclohexyl ethyl formate, is denoted as P4.Wherein the mass ratio of P3 and palladium carbon is 1:0.2(g/g).
Claims (1)
1. the synthetic method of trans-4-amino cyclohexyl ethyl formate, comprises the following steps:
(1) 4-carbonyl cyclohexyl ethyl formate is dissolved in tetrahydrofuran (THF) by feed liquid mass volume ratio 1:15 ~ 45, be cooled to-80 ℃, drip the tetrahydrofuran solution of 1mol/L 3-sec-butyl lithium borohydride L-selectride, maintain the temperature at-80 ~-70 ℃, within 2 hours, add, be incubated half an hour; Then the aqueous solution that drips mass concentration and be 8% NaOH, keeps temperature-80 ~-70 ℃, and add half an hour, and the hydrogen peroxide that to drip mass concentration be 30%, keeps temperature-80 ~-70 ℃, within 2 hours, adds; Secondly, naturally be warming up to 0 ℃, add ethyl acetate extraction, extraction times 2 times, merges organic layer, with the sodium sulfite aqueous solution that mass concentration is 10%, washs this organic layer non-oxidative, after last separatory, to described organic layer by dried over sodium sulfate to constant weight, concentrated obtain faint yellow oily matter cis-4-hydroxy-cyclohexyl ethyl formate, be denoted as P1; Wherein
The feed liquid mass volume ratio of the tetrahydrofuran solution of described 4-carbonyl cyclohexyl ethyl formate and described 1mol/L 3-sec-butyl lithium borohydride is 1:7 ~ 9; The feed liquid mass volume ratio of the aqueous solution of described 4-carbonyl cyclohexyl ethyl formate and described NaOH is 1:8 ~ 10; The feed liquid mass volume ratio of described 4-carbonyl cyclohexyl ethyl formate and described hydrogen peroxide is 1:5 ~ 8; The feed liquid mass volume ratio of described 4-carbonyl cyclohexyl ethyl formate and described ethyl acetate is 1:8 ~ 12; The volume ratio of described organic layer and described sodium sulfite aqueous solution is 1:0.05 ~ 0.2;
(2) described P1 is dissolved in methylene dichloride by feed liquid mass volume ratio 1:10 ~ 20, add triethylamine, and be cooled to-10 ℃, then drip methane sulfonyl chloride, keep temperature-10 ~ 0 ℃, within 1 hour, add, then stir 1 hour, by 5% ~ 15% of the quality of former methane sulfonyl chloride, add methane sulfonyl chloride again at 0 ℃; After half an hour, add successively water, 1mol/L aqueous hydrochloric acid, after stirring, separate organic phase; The NaCl solution washing that last described organic phase is 23% through mass concentration successively, dried over sodium sulfate, to constant weight, concentrate and obtain yellow oil cis 4-mesyloxy cyclohexyl ethyl formate, are denoted as P2; Wherein
The mass ratio of described P1 and described triethylamine is 1:1 ~ 2; The mass ratio of described P1 and described methane sulfonyl chloride is 1:0.60 ~ 1.0; The feed liquid mass volume ratio of described P1 and described water is 1:10 ~ 15; The feed liquid mass volume ratio of described P1 and described aqueous hydrochloric acid is 1:5 ~ 8;
(3) described P2 is dissolved in dimethyl formamide by feed liquid mass volume ratio 1:10 ~ 15, adds sodium azide, and be warming up to 70 ℃, stirring is spent the night; Then add water, and be extracted with ethyl acetate, extraction times 3 times, merges organic layer; This organic layer is with after the water washing of 0.05 ~ 0.2 times of its quality 2 times, through dried over sodium sulfate to constant weight, concentrated obtain red oil trans-4-azido-cyclohexyl ethyl formate, be denoted as P3; Wherein
The mass ratio of described P2 and described sodium azide is 1:0.8 ~ 1.2; The feed liquid mass volume ratio of described P2 and described water is 1:8 ~ 12; The feed liquid mass volume ratio of described P2 and described ethyl acetate is 1:8 ~ 12;
(4) described P3 is dissolved in ethanol by feed liquid mass volume ratio 1:8 ~ 12, then adding palladium mass content is 10% palladium carbon Pd/C, under the condition that is 1.0MPa at hydrogen pressure, room temperature hydrogenation is spent the night, finally filter out palladium carbon Pd/C, obtain filtrate, through concentrating under reduced pressure, obtain oily matter trans-4-amino cyclohexyl ethyl formate, be denoted as P4; The mass ratio of wherein said P3 and described palladium carbon Pd/C is 1:0.05 ~ 0.2.
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