CN106366056A

CN106366056A - Preparation method for 3-aminomethyltetrahydrofuran

Info

Publication number: CN106366056A
Application number: CN201610730578.1A
Authority: CN
Inventors: 胡锦平; 胡国宜; 郑建龙; 奚小金
Original assignee: CHANGZHOU SUNLIGHT PHARMACEUTICAL Co Ltd
Current assignee: CHANGZHOU SUNLIGHT PHARMACEUTICAL Co Ltd
Priority date: 2016-08-26
Filing date: 2016-08-26
Publication date: 2017-02-01
Anticipated expiration: 2036-08-26
Also published as: CN106366056B

Abstract

The invention discloses a preparation method for 3-aminomethyltetrahydrofuran. The preparation method comprises the following steps: with acrylonitrile as a starting material, carrying out an addition reaction with 2-halogenated ethyl alcohol so as to obtain an intermediate 2-haloethyl-2-nitrile ethyl ether; then subjecting the intermediate 2-haloethyl-2-nitrile ethyl ether to cyclic condensation so as to obtain an intermediate 3-nitrile tetrahydrofuran; and finally subjecting the intermediate 3-nitrile tetrahydrofuran to catalytic hydrogenation so as to obtain 3-aminomethyltetrahydrofuran. The preparation method provided by the invention has the advantages of cheap and easily-available starting material, short synthetic route, simple process operation, low production cost, little pollution to the human body and the environment, good yield and applicability to large-scale industrial production.

Description

The preparation method of 3- aminomethyl oxolane

Technical field

The invention belongs to catalyst preparation technical field is and in particular to a kind of preparation side of 3- aminomethyl oxolane Method.

Background technology

3- aminomethyl oxolane is that the key intermediate of synthesis third generation nicotinic insecticide MTI-446 is (special referring to Japan Sharp document jph07173157a), it is also the key intermediate of other newtype drugs (referring to international patent documents simultaneously Wo2015123365a1 and wo2015162456a1).

At present, the synthetic method of 3- aminomethyl oxolane mainly has following three kinds:

(1) with diethyl malonate and ethyl chloroacetate as initiation material, through nucleophilic in the presence of base catalyst Sodium ethylate Substitution reaction generates 1,2,2- ethane tricarboxylic acids triethyls, then becomes 2- methylol-BDO through sodium borohydride reduction, then Issue in the catalysis of acidic catalyst p-methyl benzenesulfonic acid and be conigenous body dehydration condensation and become 3- hydroxymethyl tetrahydrofuran, then with methyl sulphur Acyl chloride reaction generates 3- methanesulfonyloxymethyl oxolane, and last and the condensation of phthalimide sodium, hydrolysis are obtained.

Concrete synthetic route is as follows:

.

There is the deficiency that synthetic route is longer, total recovery is relatively low in the method, thus being not suitable for industrialized great production.

(2) with 2-butylene-Isosorbide-5-Nitrae-glycol as initiation material, through and Ketohexamethylene be condensed to yield 7,12- dioxy volution [5,6]- 9- laurylene, then insert carbonyl reaction obtain 9- formoxyl -7,12- dioxy volution [5,6] dodecane, then obtain through sodium borohydride reduction To 9- methylol -7,12- dioxy volution [5,6] dodecane, then hydrolyze and obtain 3- hydroxymethyl tetrahydrofuran, then with sulfonyloxy methyl Chlorine reaction generates 3- methanesulfonyloxymethyl oxolane, and last and the condensation of phthalimide sodium, hydrolysis are obtained.Concrete conjunction Become route as follows:

.

The method equally exists the deficiency that synthetic route is longer, total recovery is relatively low, but also there is noble metal catalyst valency Lattice are expensive and are difficult to recovery, thus being not suitable for industrialized great production.

(3) with malic acid as raw material, BT is obtained by catalytic hydrogenation, then under Catalyzed by p-Toluenesulfonic Acid Cyclisation obtain 3- hydroxyl tetrahydrofuran, then obtain 3- chlorine oxolane with thionyl chloride halo, then with Cyanogran. nucleophilic displacement of fluorine Obtain 3- itrile group oxolane, last catalytic hydrogenation obtains.

Concrete synthetic route is as follows:

.

The deficiency of the method is: malic acid price is of a relatively high and is difficult to obtain, and its catalytic hydrogenating reduction condition More harsh, operation is complex；It is in addition, nucleophilic displacement of fluorine needs the Cyanogran. using severe toxicity, larger to human body and environmental pollution, Thus being not suitable for industrialized great production.

Content of the invention

It is an object of the invention to solving the above problems, providing that a kind of raw material is cheap and easy to get, synthetic route is shorter, producing into The preparation method of this 3- aminomethyl oxolane that is relatively low, less to human body and environmental pollution, being suitable for industrialized great production.

The technical scheme realizing the object of the invention is: a kind of preparation method of 3- aminomethyl oxolane it is characterised in that Have steps of:

1. with acrylonitrile as initiation material, first carry out additive reaction with 2- ethylene halohydrin and obtain intermediate 2- halogenated ethyl -2- nitrile Benzyl ethyl ether；

2. intermediate 2- halogenated ethyl -2- itrile group ethylether obtains intermediate 3- itrile group oxolane through cyclic condensation；

3. intermediate 3- itrile group oxolane obtains 3- aminomethyl oxolane through catalytic hydrogenation.

Concrete synthetic route is as follows:

.

Above-mentioned steps 1. described in 2- ethylene halohydrin be 2- chloroethanol, 2- bromoethanol or 2- ethylene iodohydrin, excellent Elect 2- chloroethanol as.

Above-mentioned steps 1. described in the mol ratio of 2- ethylene halohydrin and described acrylonitrile be 1: 1～1: 1.

1. above-mentioned steps are carried out in the presence of base catalyst；Described base catalyst be inorganic base catalyst or Person's organic alkali catalyst, preferably inorganic base catalyst；Described inorganic base catalyst is sodium hydroxide or potassium hydroxide, preferably For sodium hydroxide；Described organic base is triethylamine, dbu(1,8- diazabicylo 11 carbon -7- alkene) or dabco(1,4- bis- Azabicyclic [2.2.2] octane), preferably triethylamine.

2. above-mentioned steps are carried out in the presence of alkali catalyst；Described alkali catalyst is Sodamide., potassamide Or sodium hydride；It is preferably Sodamide..

Above-mentioned steps 3. described in the catalyst that adopts of catalytic hydrogenation be Raney's nickel, palladium carbon or ruthenium carbon, preferably thunder Buddhist nun's nickel.

The good effect that the present invention has: the preparation method initiation material of the present invention is cheap and easy to get, and synthetic route is shorter, work Skill is simple to operate, and production cost is relatively low, less to human body and environmental pollution, and yield is preferably, thus being suitable for the big life of industrialization Produce.

Specific embodiment

(embodiment 1)

The preparation method of the 3- aminomethyl oxolane of the present embodiment has steps of:

1. add acrylonitrile 106.0g and 2- chloroethanol 161.0g in four-hole boiling flask, under stirring, be dividedly in some parts sodium hydroxide 10.0g, after adding at a temperature of 25 ± 5 DEG C insulation reaction 2h, control in sampling to raw material disappear.

Solids removed by filtration, filtrate is evaporated to dry at a temperature of 50 ± 5 DEG C, obtains colourless oil liquid 2- chloroethene Base -2- itrile group ethylether 158.6g, yield is 59.4%.

2. in four-hole boiling flask, 1. addition step is obtained 2- chloroethyl -2- itrile group ethylether 158.6g and oxolane 800ml, is cooled to 0～5 DEG C and is dividedly in some parts Sodamide. 47.2g, then heats to flow back, and insulation reaction 6h is controlled in sampling to former Material disappears.

Stop heating, be cooled to room temperature (15～25 DEG C, similarly hereinafter), reactant liquor saturated aqueous ammonium chloride is quenched, then uses Dichloromethane extracts, and organic faciess are dry through being evaporated to, and obtain pale yellowish oil liquid 3- itrile group oxolane 59.6g, yield For 51.7%.

3. add in autoclave the ammonia 200ml of 3- itrile group oxolane 59.6g, 26wt% that is 2. obtained of step and Raney's nickel 6.0g, airtight, nitrogen displacement, then leading to hydrogen is 2.5mpa to pressure, and maintains pressure, in 110 ± 5 DEG C of temperature Lower insulation reaction 5h, controls in sampling and disappears to raw material.

Filter, filtrate is concentrated to dryness, rectification under vacuum obtains colourless oil liquid 3- aminomethyl oxolane 38.5g, yield For 62.0%.

Claims

1. a kind of preparation method of 3- aminomethyl oxolane is it is characterised in that have steps of:

2. 3- aminomethyl oxolane according to claim 1 preparation method it is characterised in that: step 1. described in 2- ethylene halohydrin is 2- chloroethanol, 2- bromoethanol or 2- ethylene iodohydrin.

3. 3- aminomethyl oxolane according to claim 2 preparation method it is characterised in that: step 1. described in 2- ethylene halohydrin is 2- chloroethanol.

4. 3- aminomethyl oxolane according to claim 1 preparation method it is characterised in that: 1. step is in alkalescence Carry out in the presence of catalyst；Described base catalyst is inorganic base catalyst or organic alkali catalyst.

5. 3- aminomethyl oxolane according to claim 4 preparation method it is characterised in that: described base catalyst For inorganic base catalyst；Described inorganic base catalyst is sodium hydroxide or potassium hydroxide.

6. 3- aminomethyl oxolane according to claim 5 preparation method it is characterised in that: described inorganic base catalysiss Agent is sodium hydroxide.

7. 3- aminomethyl oxolane according to claim 1 preparation method it is characterised in that: 2. step is in highly basic Carry out in the presence of catalyst；Described alkali catalyst is Sodamide., potassamide or sodium hydride.

8. 3- aminomethyl oxolane according to claim 7 preparation method it is characterised in that: described alkali catalyst For Sodamide..

9. 3- aminomethyl oxolane according to claim 1 preparation method it is characterised in that: step 3. described in The catalyst that catalytic hydrogenation adopts is Raney's nickel, palladium carbon or ruthenium carbon.

10. 3- aminomethyl oxolane according to claim 9 preparation method it is characterised in that: step 3. described in Catalytic hydrogenation adopt catalyst be Raney's nickel.