CN102924289B - Synthetic process of hydrochloric acid trientine - Google Patents
Synthetic process of hydrochloric acid trientine Download PDFInfo
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Abstract
The invention discloses a novel synthetic process of hydrochloric acid trientine, and aims at providing the synthetic method of the hydrochloric acid trientine. The synthetic process can avoid using a highly-toxic material, namely potassium cyanide, and is temperate in reaction condition. A compound 2,2'-(2,2'-(ethane-1,2-diradical-bibenzyl-di (ethane-2,1-double radical)) bi isoindole-1,3-diketone is used as an initiator, after hydrazinolysis, an intermediate N1, N1'-(ethane-1,2-diradical) di(N1-nethyl ethane-1,2-diamine) is obtained. Through carbobenzoxy protection (Cbz protection), salt is generated,and dibenzyl 2,2'-(ethane-1,2-diradical-di (benzylamine-diradical)) di (ethane-2,1-diradical) dioctyl phthalatic acid aster hydrochloride is obtained so as to crystallize in ethanol through pressing catalytic hydrogenation deprotection to directly obtain the hydrochloric acid trientine. The synthetic process belongs to the organic synthetic technical field.
Description
Technical field
The present invention discloses a kind of synthesis technique, specifically, is a kind of synthesis technique of Syprine Hydrochloride; Belong to technical field of organic synthesis.
Background technology
About synthesizing of triethylene tetramine, there are many pieces of patents and bibliographical information, as: US4806519; US4550209; US4766247; EP450709; RU2186761; JP06065161; CZ197093; Fujito, et al, Yakuzaigagaku, 50:402-8 (1990).But the method for above-mentioned bibliographical information often needs higher temperature and pressure, the purity of product is also difficult to control.US2010/0172994A1 has reported the novel method of synthetic triethylene tetramine and salt thereof, mild condition.Synthetic route is as follows:
Route one:
Route two:
Trientine is triethylene tetramine dihydrochloride as bulk drug activeconstituents.In above-mentioned document, pass through first synthetic trientine four salt, then alkalize into free alkali, hydrogenchloride forms triethylene tetramine dihydrochloride.Because four hydrochlorides are stable compared with dihydrochloride, document adopts excessive hydrogen chloride salify, becomes the more difficult control of dihydrochloride condition.Meanwhile, the synthetic method of above-mentioned bibliographical information relates to deadly poisonous compound as the use of potassium cyanide.
Summary of the invention
For the problems referred to above, the invention provides a kind of mild condition, the synthesis technique of Syprine Hydrochloride easy and simple to handle.
Technical scheme of the present invention is such: the new synthetic process of this Syprine Hydrochloride, compound 2 with structural formula I, 2 '-(2,2 '-(ethane-1,2-bis-bases-bis-benzyls-bis-(ethane-2,1-bis-bases)) two isoindole-1,3-diketone is the Syprine Hydrochloride that starting raw material reaction obtains structural formula IV;
Structural formula I
Wherein: R
1for hydrogen atom or alkyl or-oxyl; R
2for hydrogen atom or alkyl or-oxyl or nitro;
Structural formula IV.
Further, the new synthetic process of above-mentioned a kind of Syprine Hydrochloride, comprises following preparation process successively:
1) preparation of intermediate B
Get the initiator A of structural formula I, add dehydrated alcohol and hydrazine hydrate, be heated to 60-70 ℃, reaction 15-20 hour, stirring is cooled to room temperature, suction filtration, washing, the concentrated intermediate B (N1 that obtains structural formula II, N1 '-(ethane-1,2-bis-bases) two (N1 benzyl ethane-1,2-amine)), wherein: the mol ratio of initiator A, dehydrated alcohol, hydrazine hydrate is: 1: 270-300: 5-10;
Structural formula II
Wherein: R
1for hydrogen atom or alkyl or-oxyl;
2) preparation of intermediate C
In intermediate B, add chloroform and triethylamine, cryosel is bathed cooling, drips chloroformic acid benzyl ester, at 0-5 ℃ of reaction 4-6 hour, reaction solution is transferred to separating funnel, adds anhydrous sodium sulfate drying and spend the night after washing; Suction filtration, mother liquor is concentrated, again enriched material is dissolved in to organic solvent, stirs lower dropping ethanol solution of hydrogen chloride, stir 2 hours, suction filtration, collect filter residue, wash and be dried, obtain structural formula II I intermediate C, wherein, the mol ratio of intermediate B, chloroform, triethylamine, chloroformic acid benzyl ester and ethanol solution of hydrogen chloride is 1:40-60:1.8-2.5: 1.8-2.5:1.9-2.5;
Structural formula III
Wherein: n=1 or 2, R
1for hydrogen atom or alkyl or-oxyl
3) preparation of Syprine Hydrochloride
Intermediate C is dissolved in organic solvent, add Pd/C catalyzer, pass into again hydrogen to pressure and increase to 25-35 kilogram, and maintain to react to pressure and do not drop to reaction end, collect reaction solution, suction filtration is removed Pd/C, filtrate is concentrated into dry, adds dehydrated alcohol, refrigerator cooling crystallization, suction filtration, filtration cakes torrefaction obtains Syprine Hydrochloride;
Further, the new synthetic process of above-mentioned a kind of Syprine Hydrochloride, step 1) the described hydrazine hydrate hydrazine hydrate that is 60%～80%.
The new synthetic process of above-mentioned a kind of Syprine Hydrochloride, step 2) described organic solvent is ethyl acetate; Described ethanol solution of hydrogen chloride concentration is 20～25%.
The new synthetic process of above-mentioned a kind of Syprine Hydrochloride, step 3) described organic solvent is methyl alcohol; Step 3) described catalyzer is 10%Pd/C; Step 3) add-on of described 10%Pd/C catalyzer is 5～6% of intermediate C quality.
Compared with prior art, the present invention adopts intermediate dibenzyl 2,2 '-(ethane-1; 2-bis-bases-bis-(benzylamine-bis-base)) two (ethane-2,1-bis-bases) dicarboxylic acid esters hydrochloride is raw material, through pressurized catalysis hydrogenation deprotection; crystallization in alcohol, can directly obtain Syprine Hydrochloride.Adopt above-mentioned operational path to prepare the use that Syprine Hydrochloride has been avoided violent in toxicity potassium cyanide, little to the pollution of environment, directly become the condition of dihydrochloride more easily to control, convenient operation simultaneously.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, but do not form any limitation of the invention, and the change of the unsubstantiality content that anyone makes in the claims in the present invention protection domain, still in the claims in the present invention protection domain.
Synthesis process of the present invention is:
Embodiment 1
1) preparation of intermediate B:
Initiator A: dehydrated alcohol: the mol ratio of 80% hydrazine hydrate is 1: 275:7.8.
Preparation method: add 276g initiator A:2 in being furnished with the 10L four-hole boiling flask of mechanical stirring, prolong, thermometer and drying tube, 2 '-(2,2 '-(ethane-1,2-bis-bases-bis-benzyls-bis-(ethane-2,1-bis-bases)) two isoindole-1,3-diketone, 7.5L dehydrated alcohol, 230mL80% hydrazine hydrate, under stirring, be heated to 60～70 ℃, react 18 hours, stir and be cooled to room temperature, continuous stirring 2 hours, suction filtration, filter residue absolute ethanol washing, mother liquor is evaporated to without till overhead product on Rotary Evaporators, reclaims ethanol.In bottle, solid adds appropriate dehydrated alcohol, stirs suction filtration, a small amount of absolute ethanol washing of filter residue.Merging filtrate is evaporated to dryly on Rotary Evaporators, obtains yellow oil, and this oily matter is intermediate B: N1, N1 '-(ethane-1,2-bis-bases) two (N1-benzyl ethane-1,2-diamines).
2) preparation of intermediate C
The mol ratio of intermediate B, chloroform, triethylamine, chloroformic acid benzyl ester and 22.4% ethanol solution of hydrogen chloride is 1:50.2:2.2: 2.1:2.2.
Preparation method: be furnished with again in the 5L four-hole boiling flask of thermometer, drying tube and add intermediate B (triethylene tetramines of two benzyl protections) 142g; 1.9L chloroform, 105g triethylamine, cryosel is bathed and is cooled to 0 ℃; drip chloroformic acid benzyl ester 168g; holding temperature is reacted 4 hours between 0-5 ℃, and reaction solution is transferred to separating funnel, washing; with anhydrous sodium sulfate drying, spend the night; suction filtration, collects filtrate and on Rotary Evaporators, is evaporated to without till overhead product, obtains enriched material.
Enriched material adds 1.0L ethyl acetate, dissolves, cooling in ice-water bath, stirs the ethanol solution of hydrogen chloride that the lower 170g of dropping concentration is 22.4%, separates out white solid after 0.5h, in ice-water bath, stir 2 hours, and suction filtration, filter cake washs by a small amount of ethyl acetate, and filtrate is reclaimed.By filtration cakes torrefaction, obtain white solid, i.e. intermediate C: dibenzyl 2,2 '-(ethane-1,2-bis-bases two (benzylamine-bis-base)) two (ethane-2,1-bis-bases) dicarboxylic acid esters hydrochloride.
3) preparation of Syprine Hydrochloride
The weight ratio of intermediate C, 10%Pd/C is 18.75: 1.
In 250mL autoclave pressure, add intermediate C15g, methyl alcohol 80mL, 10%Pd/C 0.8g, gets rid of the air in reactor with hydrogen, hydrogenation to 30 kilogram pressure, and till maintaining 30 kilograms of stress reactions to pressure and not declining, more slowly get rid of hydrogen in reactor.Reaction solution suction filtration is removed palladium carbon, the a small amount of methanol wash of filter residue palladium carbon, palladium carbon reclaims, and filtrate is evaporated to without till overhead product on Rotary Evaporators, in gained concentrated solution, adds 30mL dehydrated alcohol, after dissolving, add a small amount of Syprine Hydrochloride crystal seed,-18C refrigerator and cooled is crystallization but, suction filtration, a small amount of absolute ethanol washing of filter residue, dry, obtain off-white color solid Syprine Hydrochloride.
Through TOF MS and
1hNMR analyzes:
TOF MS ES:217.12 (theoretical value: 218);
1HNMR(DMSO)δ2.81(s，4H)，δ2.91-2.92(m，4H)，δ2.95-2.96(m，4H)，δ6.93(w，8H)。
The method is used intermediate dibenzyl 2,2 '-(ethane-1,2-bis-bases-bis-(benzylamine-bis-base)) two (ethane-2; 1-bis-bases) dicarboxylic acid esters hydrochloride is raw material; through pressurized catalysis hydrogenation deprotection, crystallization in alcohol, can directly obtain Syprine Hydrochloride.Adopt above-mentioned operational path to prepare the use that Syprine Hydrochloride has been avoided violent in toxicity potassium cyanide, directly become the condition of dihydrochloride with easily controlling simultaneously.
Embodiment 2
1) preparation of intermediate B:
Initiator A: dehydrated alcohol: the mol ratio of 60% hydrazine hydrate is 1: 270:10.
Preparation method: add 276g initiator A:2 in being furnished with the 10L four-hole boiling flask of mechanical stirring, prolong, thermometer and drying tube, 2 '-(2,2 '-(ethane-1,2-bis-bases-bis-benzyls-bis-(ethane-2,1-bis-bases)) two isoindole-1,3-diketone, 7.0L dehydrated alcohol, 390mL60% hydrazine hydrate, under stirring, be heated to 60～70 ℃, react 20 hours, stir and be cooled to room temperature, continuous stirring 2 hours, suction filtration, filter residue absolute ethanol washing, mother liquor is evaporated to without till overhead product on Rotary Evaporators, reclaims ethanol.In bottle, solid adds appropriate dehydrated alcohol, stirs suction filtration, a small amount of absolute ethanol washing of filter residue.Merging filtrate is evaporated to dryly on Rotary Evaporators, obtains yellow oil, and this oily matter is intermediate B: N1, N1 '-(ethane-1,2 bases) two (N1-benzyl ethane-1,2-amine).
2) preparation of intermediate C
The mol ratio of intermediate B, chloroform, triethylamine, chloroformic acid benzyl ester and 25% ethanol solution of hydrogen chloride is 1:40:1.8: 1.8:1.9.
Preparation method: add intermediate B (triethylene tetramines of two benzyl protections) 142g in being furnished with the 5L four-hole boiling flask of thermometer, drying tube; 1.5L chloroform, 86g triethylamine, cryosel is bathed and is cooled to 0 ℃; drip chloroformic acid benzyl ester 145g; holding temperature is reacted 6 hours between 0-5 ℃, and reaction solution is transferred to separating funnel, washing; with anhydrous sodium sulfate drying, spend the night; suction filtration, collects filtrate and on Rotary Evaporators, is evaporated to without till overhead product, obtains enriched material.
Enriched material adds 1.0L ethyl acetate, dissolves, cooling in ice-water bath, stirs the ethanol solution of hydrogen chloride that the lower 130g of dropping concentration is 25%, separates out white solid after 0.5h, in ice-water bath, stir 2 hours, and suction filtration, filter cake washs by a small amount of ethyl acetate, and filtrate is reclaimed.By filtration cakes torrefaction, obtain white solid, i.e. intermediate C: dibenzyl 2,2 '-(ethane-1,2-bis-bases-bis-(benzylamine two bases)) two (ethane-2,1-bis-bases) dicarboxylic acid esters hydrochloride.
3) preparation of Syprine Hydrochloride
The weight ratio of intermediate C, 10%Pd/C is 20: 1.
In 250mL autoclave pressure, add intermediate C15g, methyl alcohol 80mL, 10%Pd/C 0.75g, gets rid of the air in reactor with hydrogen, hydrogenation to 25 kilogram pressure, and till maintaining 25 kilograms of stress reactions to pressure and not declining, more slowly get rid of hydrogen in reactor.Reaction solution suction filtration is removed palladium carbon, the a small amount of methanol wash of filter residue palladium carbon, palladium carbon reclaims, and filtrate is evaporated to without till overhead product on Rotary Evaporators, in gained concentrated solution, adds 30mL dehydrated alcohol, after dissolving, add a small amount of Syprine Hydrochloride crystal seed,-18 ℃ of refrigerator and cooled are crystallization but, suction filtration, a small amount of absolute ethanol washing of filter residue, dry, obtain off-white color solid Syprine Hydrochloride.
Embodiment 3
1) preparation of intermediate B:
Initiator A: dehydrated alcohol: the mol ratio of 70% hydrazine hydrate is 1: 300:7.
Preparation method: add 276g initiator A:2 in being furnished with the 10L four-hole boiling flask of mechanical stirring, prolong, thermometer and drying tube, 2 '-(2,2 ' _ (ethane-1,2-bis-bases-bis-benzyls-bis-(ethane-2,1-bis-bases)) two isoindole-1,3-diketone, 8.3L dehydrated alcohol, 235mL70% hydrazine hydrate, under stirring, be heated to 60～70 ℃, react 15 hours, stir and be cooled to room temperature, continuous stirring 2 hours, suction filtration, filter residue absolute ethanol washing, mother liquor is evaporated to without till overhead product on Rotary Evaporators, reclaims ethanol.In bottle, solid adds appropriate dehydrated alcohol, stirs suction filtration, a small amount of absolute ethanol washing of filter residue.Merging filtrate is evaporated to dryly on Rotary Evaporators, obtains yellow oil, and this oily matter is intermediate B.
2) preparation of intermediate C
The mol ratio of intermediate B, chloroform, triethylamine, chloroformic acid benzyl ester and 20% ethanol solution of hydrogen chloride is 1:60:2.5: 2.5:2.5.
Preparation method: add intermediate B (triethylene tetramines of two benzyl protections) 142g in being furnished with the 5L four-hole boiling flask of thermometer, drying tube; 2.3L chloroform, 120g triethylamine, cryosel is bathed and is cooled to 0 ℃; drip chloroformic acid benzyl ester 200g; holding temperature is reacted 5 hours between 0-5 ℃, and reaction solution is transferred to separating funnel, washing; with anhydrous sodium sulfate drying, spend the night; suction filtration, collects filtrate and on Rotary Evaporators, is evaporated to without till overhead product, obtains enriched material.
Enriched material adds 1.0L ethyl acetate, dissolves, cooling in ice-water bath, stirs the ethanol solution of hydrogen chloride that the lower 215g of dropping concentration is 20%, separates out white solid after 0.5h, in ice-water bath, stir 2 hours, and suction filtration, filter cake washs by a small amount of ethyl acetate, and filtrate is reclaimed.By filtration cakes torrefaction, obtain white solid, i.e. intermediate C.
3) preparation of Syprine Hydrochloride
The weight ratio of intermediate C, 10%Pd/C is 16.7: 1.
In 250mL autoclave pressure, add intermediate C15g, methyl alcohol 80mL, 10%Pd/C 0.9g, gets rid of the air in reactor with hydrogen, hydrogenation to 35 kilogram pressure, and till maintaining 35 kilograms of stress reactions to pressure and not declining, more slowly get rid of hydrogen in reactor.Reaction solution suction filtration is removed palladium carbon, the a small amount of methanol wash of filter residue palladium carbon, palladium carbon reclaims, and filtrate is evaporated to without till overhead product on Rotary Evaporators, in gained concentrated solution, adds 30mL dehydrated alcohol, after dissolving, add a small amount of Syprine Hydrochloride crystal seed,-18 ℃ of refrigerator and cooled are crystallization but, suction filtration, a small amount of absolute ethanol washing of filter residue, dry, obtain off-white color solid Syprine Hydrochloride.
Embodiment 4
2) preparation of intermediate B:
Initiator A: dehydrated alcohol: the mol ratio of 80% hydrazine hydrate is 1: 285:5.
Preparation method: add 276g initiator A:2 in being furnished with the 10L four-hole boiling flask of mechanical stirring, prolong, thermometer and drying tube, 2 '-(2,2 '-(ethane-1,2-bis-bases-bis-benzyls-bis-(ethane-2,1-bis-bases)) two isoindole-1,3-diketone, 7.8L dehydrated alcohol, 150mL80% hydrazine hydrate, under stirring, be heated to 60～70 ℃, react 18 hours, stir and be cooled to room temperature, continuous stirring 2 hours, suction filtration, filter residue absolute ethanol washing, mother liquor is evaporated to without till overhead product on Rotary Evaporators, reclaims ethanol.In bottle, solid adds appropriate dehydrated alcohol, stirs suction filtration, a small amount of absolute ethanol washing of filter residue.Merging filtrate is evaporated to dryly on Rotary Evaporators, obtains yellow oil, and this oily matter is intermediate B.
2) preparation of intermediate C
The mol ratio of intermediate B, chloroform, triethylamine, chloroformic acid benzyl ester and 22.4% ethanol solution of hydrogen chloride is 1:45:2.0: 2.0:2.0.
Preparation method: add intermediate B (triethylene tetramines of two benzyl protections) 142g in being furnished with the 5L four-hole boiling flask of thermometer, drying tube; 1.7L chloroform, 95g triethylamine, cryosel is bathed and is cooled to 0 ℃; drip chloroformic acid benzyl ester 160g; maintain the temperature between 0-5 ℃ and react 4 hours, reaction solution is transferred to separating funnel, washing; with anhydrous sodium sulfate drying, spend the night; suction filtration, collects filtrate and on Rotary Evaporators, is evaporated to without till overhead product, obtains enriched material.
Enriched material adds 1.0L ethyl acetate, dissolves, cooling in ice-water bath, stirs the ethanol solution of hydrogen chloride that the lower 155g of dropping concentration is 22.4%, separates out white solid after 0.5h, in ice-water bath, stir 2 hours, and suction filtration, filter cake washs by a small amount of ethyl acetate, and filtrate is reclaimed.By filtration cakes torrefaction, obtain white solid, i.e. intermediate C.
3) preparation of Syprine Hydrochloride
The weight ratio of intermediate C, 10%Pd/C is 18.07: 1.In 250mL autoclave pressure, add intermediate C 15g, methyl alcohol 80mL, 10%Pd/C0.83g, gets rid of the air in reactor with hydrogen, hydrogenation to 30 kilogram pressure, and till maintaining 30 kilograms of stress reactions to pressure and not declining, more slowly get rid of hydrogen in reactor.Reaction solution suction filtration is removed palladium carbon, the a small amount of methanol wash of filter residue palladium carbon, palladium carbon reclaims, and filtrate is evaporated to without till overhead product on Rotary Evaporators, in gained concentrated solution, adds 30mL dehydrated alcohol, after dissolving, add a small amount of Syprine Hydrochloride crystal seed,-18C refrigerator and cooled is crystallization but, suction filtration, a small amount of absolute ethanol washing of filter residue, dry, obtain off-white color solid Syprine Hydrochloride.
Claims (7)
1. a synthesis technique for Syprine Hydrochloride, is characterized in that, with the compound 2 of structural formula I, 2'-(2,2'-(ethane-1,2-bis-bases-bis-benzyls-bis-(ethane-2,1-bis-bases)) two isoindole-1,3-diketone is starting raw material, reaction obtains structural formula IV Syprine Hydrochloride;
Wherein: R
1for hydrogen atom or alkyl or-oxyl; R
2for hydrogen atom or alkyl or-oxyl or nitro;
Specifically comprise the steps:
1) preparation of intermediate B
Get the initiator A of structural formula I, add dehydrated alcohol and hydrazine hydrate, be heated to 60-70 ℃, reaction 15-20 hour, stirring is cooled to room temperature, suction filtration, washing, the concentrated intermediate B N1 that obtains structural formula II, N1'-(ethane-1,2-bis-bases) two (N1-benzyl ethane-1,2-diamines), wherein: the mol ratio of initiator A, dehydrated alcohol, hydrazine hydrate is: 1 ﹕ 270-300 ﹕ 5-10;
Wherein: R
1for hydrogen atom or alkyl or-oxyl;
2) preparation of intermediate C
In intermediate B, add chloroform and triethylamine, cryosel is bathed cooling, drips chloroformic acid benzyl ester, at 0-5 ℃ of reaction 4-6 hour, reaction solution is transferred to separating funnel, adds anhydrous sodium sulfate drying and spend the night after washing; Suction filtration, mother liquor is concentrated, again enriched material is dissolved in to organic solvent, stirs lower dropping ethanol solution of hydrogen chloride, stir 2 hours, suction filtration, collect filter residue, wash and be dried, obtain structural formula III intermediate C, wherein, the mol ratio of intermediate B, chloroform, triethylamine, chloroformic acid benzyl ester and ethanol solution of hydrogen chloride is 1:40-60:1.8-2.5:1.8-2.5:1.9-2.5;
Wherein: n=1 or 2, R
1for hydrogen atom or alkyl or-oxyl
3) preparation of Syprine Hydrochloride
Intermediate C is dissolved in organic solvent, add Pd/C catalyzer, pass into again hydrogen to pressure and increase to 25-35 kilogram, and maintain to react to pressure and do not drop to reaction end, collect reaction solution, suction filtration is removed Pd/C, filtrate adds dehydrated alcohol, refrigerator cooling crystallization after being concentrated into and doing, suction filtration, filtration cakes torrefaction obtains Syprine Hydrochloride.
2. the synthesis technique of a kind of Syprine Hydrochloride according to claim 1, is characterized in that step 1) the described hydrazine hydrate hydrazine hydrate that is 60%-80%.
3. the synthesis technique of a kind of Syprine Hydrochloride according to claim 1, is characterized in that step 2) described ethanol solution of hydrogen chloride concentration is 20-25%.
4. the synthesis technique of a kind of Syprine Hydrochloride according to claim 1, is characterized in that step 2) described organic solvent is ethyl acetate.
5. the synthesis technique of a kind of Syprine Hydrochloride according to claim 1, is characterized in that step 3) described organic solvent is methyl alcohol.
6. the synthesis technique of a kind of Syprine Hydrochloride according to claim 1, is characterized in that step 3) described catalyzer is 10%Pd/C.
7. the synthesis technique of a kind of Syprine Hydrochloride according to claim 6, is characterized in that step 3) add-on of described 10%Pd/C catalyzer is the 5-6% of intermediate C quality.
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| WO2017046695A1 (en) * | 2015-09-18 | 2017-03-23 | Emcure Pharmaceuticals Limited | An improved process for preparation of trientine dihydrochloride |
| CN108164427B (en) * | 2017-12-27 | 2020-12-04 | 云南民族大学 | Synthetic method of trientine hydrochloride |
| US20230192591A1 (en) * | 2020-03-27 | 2023-06-22 | Daniel J. Coughlin | Process for preparing trientine dihydrochloride |
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