CN104193654B - The preparation method of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride - Google Patents
The preparation method of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride Download PDFInfo
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Abstract
The invention belongs to organic chemical industry field, be specifically related to the preparation method of a kind of 1 (3 dimethylamino-propyl) 3 ethyl-carbodiimide hydrochlorides.N, N ' dimethylated propyl diethylenetriamine and Carbon bisulfide is that raw material reacts in organic solvent, generates intermediate 1；Intermediate 1 and ethyl chloroformate react in organic solvent, and triethylamine, as acid binding agent, prepares intermediate 2；Intermediate 2 and ethamine react in organic solvent, prepare intermediate 3；Intermediate 3 adds catalyst, carries out once oxidation with oxidant, obtain crude product 1 (3 dimethylamino-propyl) 3 ethyl carbodiimide, extract and separate, obtain intermediate 4；Intermediate 4 and hydrochlorate carry out salt exchange reaction and prepare product 1 (3 dimethylamino-propyl) 3 ethyl-carbodiimide hydrochlorides.The present invention has higher conversion ratio, and total recovery is higher, simple to operate, is suitable for industrialized production.
Description
Technical field
The invention belongs to organic chemical industry field, be specifically related to a kind of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
Preparation method.
Background technology
1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, is called for short EDC hydrochlorate, molecular formula: C8H17N3HCl,
Structural formula is:
Relative molecular mass is 191.70, white crystalline powder, the easily moisture absorption, dissolubility in water > 20g/100ml, it is dissolved in ethanol, molten
Point 110-114 DEG C, is used as the activating reagent of carboxyl in amide synthesizes, and is also used for activated phosphate group, protein and nucleic acid
Crosslinking is produced with the coupled thing of immunity.PH scope during use is 4.0-6.0, normal and N-hydroxy-succinamide (NHS) or N-
Hydroxy thiosuccinimide is used in conjunction, to improve coupling efficiency.
The preparation method of traditional 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide is as follows:
Synthetic method one: at document Organic Syntheses, Coll.Vol.5, p.555 (1973)；Vol.48, p.83 in (1968) with
Ethyl isocyanate is raw material, then ethyl isocyanate and N, and carbamide prepared by N '-dimethyl propane diamine, and then dehydration prepares product, receives
Rate is 40%.
This synthetic method yield is relatively low, and raw material paratoluensulfonyl chloride is expensive, is not suitable for industrialized production.
Synthetic method United States Patent (USP) US3135748 of 2: 1964 years proposes with isothiocyanate as initiation material, then by sulfonic acid chloride
Desulfurization prepares product.
In this synthetic method, raw materials used sulfonic acid chloride is expensive, seriously polluted, is not suitable for industrialized production.
The synthetic method Japan Patent JPH08198836A of 3: 1996 years proposes to prepare ethyl mustard oil. with ethamine for raw material,
Then with N, N '-dimethyl propane diamine reacts, and prepares product, yield 32% by hypochlorite oxidation.
This method yield is relatively low, is not suitable for industrialized production.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, improve
The yield of product and purity, reduce cost, is suitable for industrialized production.
The preparation method of 1-of the present invention (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, step is as follows:
(1) N, N '-dimethyl propane diamine and Carbon bisulfide are raw material, react in organic solvent at 10-15 DEG C, generate intermediate 1；
(2) intermediate 1 and ethyl chloroformate 10-15 DEG C of reaction in organic solvent, triethylamine, as acid binding agent, prepares intermediate 2；
(3) intermediate 2 and ethamine 10-15 DEG C of reaction in organic solvent, prepare intermediate 3；
(4) intermediate 3 adds catalyst, at 20-30 DEG C, carry out once oxidation with oxidant, obtain crude product 1-(3-diformazan ammonia
Base propyl group)-3-ethyl carbodiimide, extract and separate, obtain intermediate 4；
(5) intermediate 4 and hydrochlorate carry out salt exchange reaction and prepare product 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride
Salt.
N described in step (1), N '-dimethyl propane diamine is 1:1.1-1.13 with the mol ratio of Carbon bisulfide.
Organic solvent described in step (1) is methanol or chloroform, and the volume of organic solvent is 5-10 times of Carbon bisulfide volume.
Ethyl chloroformate described in step (2) and N, the mol ratio of N '-dimethyl propane diamine is 1.05-1:1.
N described in step (2), N '-dimethyl propane diamine is 1:1-1.2 with the mol ratio of triethylamine；Organic solvent is chloroform
Or dichloromethane, the volume of organic solvent is 4-8 times of Carbon bisulfide volume.
Ethamine described in step (3) and N, the mol ratio of N '-dimethyl propane diamine is 0.99-1.1:1.
Organic solvent described in step (3) is chloroform or dichloromethane, and the volume of organic solvent is the 5-10 of Carbon bisulfide volume
Times.
Catalyst described in step (4) is EDTA or TEBA, and the quality of catalyst is the 0.05-0.09% of the quality of ethamine.
Oxidant described in step (4) is sodium hypochlorite, oxidant and N, and the mol ratio of N '-dimethyl propane diamine is 1.8-2.5:
1。
Hydrochlorate described in step (5) is the one in triethylamine hydrochloride, pyridine hydrochloride or ammonium chloride.
The production technology of 1-of the present invention (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, is with N, N '-dimethyl propane diamine
Be raw material with Carbon bisulfide, reaction prepare N, N '-dimethyl propyl group sulfydryl thiourea, then with ethyl chloroformate oxidation prepare N, N '-
Dimethyl propyl isothiocyanate, then react with ethamine, obtain crude product 1-(3-dimethylamino-propyl)-3-through hypochlorite oxidation
Ethyl carbodiimide, crude product carries out salt exchange reaction prepare product 1-(3-dimethylamino-propyl)-3-with organic salt hydrochlorate or inorganic salt
Ethyl-carbodiimide hydrochloride.The present invention improves each step conversion ratio and improves yield and the purity of product, reduces cost so that be suitable for
Industrialized production.
Correlated response formula is as follows:
The preparation method of 1-of the present invention (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, specifically comprises the following steps that
First step N, N '-dimethyl propane diamine and Carbon bisulfide are raw material, react in organic solvent, generate intermediate 1.
Reaction temperature is at about 10-15 DEG C, and by N, N '-dimethyl propane diamine is slowly dropped in Carbon bisulfide, drips complete insulation 1
Hour, filter, obtain white solid (intermediate 1).
Intermediate 1 and ethyl chloroformate are reacted in organic solvent by second step, and triethylamine, as acid binding agent, prepares intermediate 2.
Ethyl chloroformate, at about 10-15 DEG C, is slowly dropped in intermediate 1 by reaction temperature, drips complete, is incubated 1 hour,
Molten clearly to reactant liquor, then extract and separate goes out organic facies, is dried, and i.e. obtains intermediate 2.
3rd step intermediate 2 and ethamine react and prepare intermediate 3.
Reaction temperature is about 10 DEG C, is slowly dropped in ethamine organic solvent by intermediate 2, drips complete, is incubated 1 hour,
By pH=11-12 alkali liquid washing organic facies, i.e. intermediate 3, organic facies directly carries out lower step oxidation sweetening；Solvent mainly have aromatic hydrocarbons,
Benzene, dimethylbenzene, halogenated hydrocarbon, chloroform, dichloromethane etc..
The intermediate 3 that 4th step obtains adds catalyst oxidant and carries out once oxidation, obtains crude product 1-(3-dimethylamino third
Base)-3-ethyl carbodiimide, extract and separate, obtain intermediate 4.
The intermediate 4 that 5th step obtains carries out salt exchange reaction prepare product E DC hydrochloric acid with organic salt hydrochlorate or inorganic salt hydrochlorate
Salt, wherein hydrochlorate includes triethylamine hydrochloride, pyridine hydrochloride, ammonium chloride etc..
The present invention compared with prior art, has the advantages that
The present invention is initiation material with N, N '-dimethyl propane diamine and Carbon bisulfide, oxidized, condensation, oxidation sweetening, one-tenth salt four
Step reaction, obtains EDC hydrochlorate, total recovery 80%；This technique has higher conversion ratio, and total recovery is higher, simple to operate,
It is suitable for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
Weigh Carbon bisulfide 12ml to be dissolved in 100ml methanol, be slowly added dropwise N, N '-dimethyl propane diamine 20.4g, control temperature
At 10-15 DEG C, dropping process has white solid to generate, drip complete in 10-15 DEG C be incubated 1 hour, filter, use methanol foam washing,
Obtain white solid 38g (intermediate 1), yield 95%.
Weighing step product 38g, add 120ml chloroform, control temperature, at 10-15 DEG C, adds triethylamine 24.2g, then delays
Slow dropping 11.1g ethyl chloroformate, drips 1 hour, drips complete insulation 1 hour, washs organic facies clearly to molten, filters,
It is dried to obtain product (intermediate 2).
Weigh ethamine 12.9g (containing water 70%), add 60ml chloroform, be cooled to 10-15 DEG C, be slowly added dropwise intermediate 2,
Drip complete insulation 1 hour, by the alkali liquid washing organic facies of pH=11-12, be dried, decompression, concentrate, obtain grease 31.6g,
(intermediate 3), adds 0.012gTEBA, at 25 DEG C, aoxidizes with the sodium hypochlorite 270g that mass concentration is 10%, oxygen
Change complete, extracting and demixing, organic facies reduces pressure after drying and concentrates at 30 DEG C, and after solvent is evaporated, rectification under vacuum obtains EDC25g,
Purity 99.2%；
Weigh triethylamine hydrochloride 39g, add 100ml dichloromethane, control, at 30 DEG C, to be slowly added dropwise the EDC that rectification obtains,
Elder generation is the most molten separates out crystal clearly the most again, drips complete, is cooled to 5 DEG C, and crystallize 1h filters, obtains 30.56gEDC hydrochlorate,
Purity 99.5%, yield 80.4% (with N, N '-dimethyl propane diamine meter).
Embodiment 2
Weigh Carbon bisulfide 24ml to be dissolved in 150ml methanol, be slowly added dropwise N, N '-dimethyl propane diamine 43.8g, control temperature
At 10-15 DEG C, dropping process has white solid to generate, drip complete in 20 DEG C be incubated 2 hours, filter, use methanol foam washing,
Obtain white solid 75g (intermediate 1), yield 96%.
Weighing step product 75g, add 200ml dichloromethane, control temperature, at 10-15 DEG C, adds triethylamine 45.8g, so
After be slowly added dropwise 50.3g ethyl chloroformate, drip 2 hours, drip complete insulation 1 hour, to the most molten clearly, wash organic facies,
Filter, be dried to obtain product (intermediate 2).
Weigh ethamine 25.2g (containing water 70%), add 180ml dichloromethane, be cooled to 10-15 DEG C, be slowly added dropwise centre
Body 2, drips complete insulation 1 hour, by the alkali liquid washing organic facies of pH=11-12, is dried, decompression, concentrates, obtain oily
Thing 90g, (intermediate 3), add 0.02gEDTA, 30 DEG C, aoxidize with the sodium hypochlorite 630g that mass concentration is 10%,
Aoxidizing complete, extracting and demixing, organic facies reduces pressure after drying and concentrates at 30 DEG C, and after solvent is evaporated, rectification under vacuum obtains EDC, pure
Degree 99.4%；
Weigh pyridine hydrochloride 41.4g, add 120ml dichloromethane, control, at 30 DEG C, to be slowly added dropwise the EDC that rectification obtains,
Elder generation is the most molten separates out crystal clearly the most again, drips complete, is cooled to 5 DEG C, and crystallize 1h filters, obtains 71.2gEDC hydrochlorate,
Purity 99.5%, yield 81% (with N, N '-dimethyl propane diamine meter).
Embodiment 3
Weigh Carbon bisulfide 24ml to be dissolved in 150ml chloroform, be slowly added dropwise N, N '-dimethyl propane diamine 41.5g, control temperature
At 10-15 DEG C, drip complete in 15 DEG C of insulations 1 hour, concentrating under reduced pressure, obtain white solid 72.4g (intermediate 1).
By upper step white solid product 72.4, adding 180ml chloroform, control temperature, at 10-15 DEG C, adds triethylamine 41.2g,
Then it is slowly added dropwise 48.9g ethyl chloroformate, drips 2 hours, drip complete insulation 1 hour, wash organic facies clearly to molten,
Filter, be dried to obtain product (intermediate 2).
Weigh ethamine 26.2g (containing water 70%), add 150ml dichloromethane, be cooled to 10-15 DEG C, be slowly added dropwise centre
Body 2, drips complete insulation 1 hour, by the alkali liquid washing organic facies of pH=11-12, is dried, decompression, concentrates, obtain oily
Thing 108g (intermediate 3), adds 0.015gTEBA, 20 DEG C, carries out oxygen with the sodium hypochlorite 680g that mass concentration is 10%
Change, aoxidize complete, extracting and demixing, organic facies reduces pressure after drying and concentrates at 30 DEG C, and after solvent is evaporated, rectification under vacuum obtains EDC,
Purity 99.4%；
Weigh ammonium chloride 17.4g, add 130ml dichloromethane, control, below 30 DEG C, to be slowly added dropwise the EDC that rectification obtains,
Elder generation is the most molten separates out crystal clearly the most again, drips complete, is cooled to 5 DEG C, and crystallize 1h filters, obtains 62.3gEDC hydrochlorate,
Purity 99.5%, yield 80% (with N, N '-dimethyl propane diamine meter).
Claims (8)
1. the preparation method of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterised in that step is as follows:
(1) N, N '-dimethyl propane diamine and Carbon bisulfide are raw material, react in organic solvent at 10-15 DEG C, generate intermediate 1；
(2) intermediate 1 and ethyl chloroformate 10-15 DEG C of reaction in organic solvent, triethylamine, as acid binding agent, prepares intermediate 2；
(3) intermediate 2 and ethamine 10-15 DEG C of reaction in organic solvent, prepare intermediate 3；
(4) intermediate 3 adds catalyst, at 20-30 DEG C, carry out once oxidation with oxidant, obtain crude product 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, extract and separate, obtain intermediate 4；
(5) intermediate 4 and hydrochlorate carry out salt exchange reaction and prepare product 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride；
Catalyst described in step (4) is EDTA or TEBA, and the quality of catalyst is the 0.05-0.09% of the quality of ethamine；
Oxidant described in step (4) is sodium hypochlorite, oxidant and N, and the mol ratio of N '-dimethyl propane diamine is 1.8-2.5:1.
The preparation method of 1-the most according to claim 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterised in that the N described in step (1), N '-dimethyl propane diamine is 1:1.1-1.13 with the mol ratio of Carbon bisulfide.
The preparation method of 1-the most according to claim 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterized in that the organic solvent described in step (1) is methanol or chloroform, the volume of organic solvent is 5-10 times of Carbon bisulfide volume.
The preparation method of 1-the most according to claim 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterised in that the ethyl chloroformate described in step (2) and N, the mol ratio of N '-dimethyl propane diamine is 1.05-1:1.
The preparation method of 1-the most according to claim 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterised in that the N described in step (2), N '-dimethyl propane diamine is 1:1-1.2 with the mol ratio of triethylamine；Organic solvent is chloroform or dichloromethane, and the volume of organic solvent is 4-8 times of Carbon bisulfide volume.
The preparation method of 1-the most according to claim 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterised in that the ethamine described in step (3) and N, the mol ratio of N '-dimethyl propane diamine is 0.99-1.1:1.
The preparation method of 1-the most according to claim 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterized in that the organic solvent described in step (3) is chloroform or dichloromethane, the volume of organic solvent is 5-10 times of Carbon bisulfide volume.
The preparation method of 1-the most according to claim 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, it is characterised in that the hydrochlorate described in step (5) is the one in triethylamine hydrochloride, pyridine hydrochloride or ammonium chloride.
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| CN107954909A (en) * | 2017-12-14 | 2018-04-24 | 山东汇海医药化工有限公司 | A kind of method that isothiocyanates is prepared using ethyl chloroformate |
| CN107954910B (en) * | 2017-12-15 | 2019-08-02 | 山东金城医药化工有限公司 | The method of simultaneously synthesizing N, N- dimethyl-ethylenediamine isothiocyanates and thioacetic acid |
| CN109517590B (en) * | 2018-05-29 | 2020-12-01 | 吉林化工学院 | Graphene grafted acrylamide polymer oil displacement agent for pressure swing displacement and preparation method thereof |
| CN109053494A (en) * | 2018-08-29 | 2018-12-21 | 山东金城柯瑞化学有限公司 | The method of purification of 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride |
| CN109369458A (en) * | 2018-09-14 | 2019-02-22 | 山东金城柯瑞化学有限公司 | The preparation method of 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride |
| CN109400503A (en) * | 2018-11-01 | 2019-03-01 | 山东汇海医药化工有限公司 | A method of improving 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCI m. p |
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| JPH08198836A (en) * | 1995-01-26 | 1996-08-06 | Sanshin Chem Ind Co Ltd | Production of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide |
| JPH08277254A (en) * | 1995-04-05 | 1996-10-22 | Sanshin Chem Ind Co Ltd | Purification of 1-ethyl-3-(3dimethylaminopropyl) carbodiimide |
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| US3135748A (en) * | 1960-05-27 | 1964-06-02 | Little Inc A | Heterocyclic substituted carbodhmides and method of preparation |
| GB1259003A (en) * | 1968-01-20 | 1972-01-05 | ||
| CN102643215A (en) * | 2012-04-20 | 2012-08-22 | 济南圣泉唐和唐生物科技有限公司 | Preparation method of carbodiimide |
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