CN102336676A - New preparation method of dopexamine hydrochloride by ArCHR protection strategy - Google Patents

New preparation method of dopexamine hydrochloride by ArCHR protection strategy Download PDF

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CN102336676A
CN102336676A CN201010227799XA CN201010227799A CN102336676A CN 102336676 A CN102336676 A CN 102336676A CN 201010227799X A CN201010227799X A CN 201010227799XA CN 201010227799 A CN201010227799 A CN 201010227799A CN 102336676 A CN102336676 A CN 102336676A
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acid
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potassium
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许佑君
马占芝
张华�
李亚玲
惠帅
杨吉宁
孙静
丁百莲
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SHUANGDING PHARMACEUTICAL CO Ltd SHENYANG
Shenyang Pharmaceutical University
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SHUANGDING PHARMACEUTICAL CO Ltd SHENYANG
Shenyang Pharmaceutical University
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Abstract

本发明属于制药领域，涉及盐酸多培沙明(1)的新制备方法，及双芳甲基保护的盐酸多培沙明(I)与制备方法。本发明利用芳甲基保护策略，先制备双芳甲基保护的盐酸多培沙明(I)，然后利用催化氢化，于温和条件下选择性地脱除相应的芳甲基保护基，得到盐酸多培沙明。 The invention belongs to the field of pharmacy, and relates to a new preparation method of dopexamine hydrochloride (1), and dopexamine hydrochloride (I) protected by a bisarylmethyl group and a preparation method. The present invention utilizes an arylmethyl protection strategy to first prepare bisarylmethyl-protected dopexamine hydrochloride (I), and then uses catalytic hydrogenation to selectively remove the corresponding arylmethyl protecting group under mild conditions to obtain hydrochloric acid Dopexamine.

Description

Utilize the FPL-60278AR new preparation process of arylmethyl protection strategy
Technical field
The invention belongs to pharmacy field, relate to the FPL-60278AR new preparation process that utilizes arylmethyl protection strategy.
Background technology
FPL-60278AR is an adrenomimetic drug class medicine, and chemical structure is similar with Dopamine HCL, and very strong β is arranged 2The excitation of-adrenergic receptor, ability is the expansion artery blood vessel significantly, can increase the blood flow of cardiac muscle, kidney, liver, Skelettmuskel, reduces cardiac afterload; To heart β 1A little less than-adrenergic receptor and the Dopamine Receptors excitation, myocardial contraction is strengthened, heart rate is accelerated, and slight natriuretic diuretic effect is arranged.Be applicable to the low patient of cardiac output after treatment acute heart failure and the heart operation.
Fisons company once was that raw material prepares FPL-60278AR (EP0117033A2) with the hexanodioic acid; Hexanodioic acid is successively with 3; 4-dimethoxy-phenylethylamine and phenylethylamine reaction, the midbody of formation biamide structure, the bisamide in this midbody obtain the dopexamine of bi-methoxy protection through reduction; Last demethylating protection base can synthesize dopexamine.But the demethylation condition is harsh, need in hydrobromic acid solution, high temperature, long-time reaction can carry out, and by product is many; Yield lower (57.6%), and what obtain is the hydrobromate of dopexamine; Need in the alkali and discharge, and then form needed hydrochloride form, in the alkali when discharging; The oxidation especially easily of in the dopexamine molecule 1,2-dihydroxy-benzene structure forms the quinoid by product.
People such as Lu Jinrong (China Medicine University's journal, 1999,30 (5); 328～331) elder generation is with the acyl chlorides and the 6-aminocaprolc acid reaction of toluylic acid; Corresponding carboxylic acid and 3, the condensation of 4-dimethoxy-phenylethylamine also can form the biamide structure midbody; After the bisamide reduction, obtain the dopexamine of bi-methoxy protection.Discharge via similar demethyl method, neutralization, become hydrochloride at last, obtain FPL-60278AR, total recovery is 16.8%.This seminar has reported that also another is the synthetic route of raw material with the hexanodioic acid; Compare with Fisons company route; Hexanodioic acid becomes earlier acid amides with phenylethylamine, again with 3; The 4-dimethoxy-phenylethylamine becomes second acid amides, and the bisamide midbody comes the synthetic hydrochloric acid dopexamine through similar processing, and total recovery is 24.5%.
In sum; Three routes having reported all adopt 1 of methyl protection correspondence, and structural pair of hydroxyl of 2-dihydroxy-benzene needs high temperature removal methyl protection base in hydrobromic acid solution at last; Gained Hydrogen bromide dopexamine needs in alkali and discharges, and becomes hydrochloride to come the synthetic hydrochloric acid dopexamine again.The demethylating reaction condition is harsh, and temperature is high, use duration, and by product is many, and when neutralization discharged, under the alkalescence 1,2-dihydroxy-benzene structure was prone to be oxidized to the quinoid by product.
Summary of the invention
The present invention relates to the new preparation process of FPL-60278AR (1); Utilize arylmethyl (ArCHR) protection strategy; Hydrochloric acid
Figure 201010227799X1000021
dopexamine (I) of the two arylmethyl protections of preparation earlier; Under mild conditions, utilize catalytic hydrogenation then; Optionally remove corresponding arylmethyl protection base, directly obtain the hydrochloride of dopexamine.Ar can be: phenyl, methyl substituted phenyl, the substituted phenyl of methoxyl group; The substituted phenyl of nitro, fluorine, chlorine, the substituted phenyl of bromine or iodine, fragrant heterocycle such as pyridine, thiophene, furans; 1-naphthyl or 2-naphthyl; Methyl substituted 1-naphthyl or 2-naphthyl, substituted 1-naphthyl of nitro or 2-naphthyl, fluorine, chlorine, the substituted 1-naphthyl of bromine or iodine or 2-naphthyl; R can be: hydrogen, methyl or phenyl; Said Ar is preferably phenyl and R is preferably hydrogen.
First purpose of the present invention is, in solvent, is catalyzer with the transition metal, and hydrochloride (I) catalytic hydrogenation with the two arylmethyl protection dopexamines behind the purifying removes arylmethyl protection base, obtains FPL-60278AR.The used transition-metal catalyst of this reaction can be palladium, ruthenium, rhodium or nickel etc.; For improving the catalytic activity of these catalyzer, can be on carrier with these metal loads, carrier can be gac, zeyssatite, molecular sieve, aluminum oxide or silica gel etc.; The solvent that reacts used can be selected alcohols such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol or the trimethyl carbinol of 1～6 carbon; Perhaps ether property solvent such as ether, MTBE, Di Iso Propyl Ether, THF, 2-methyltetrahydrofuran, 1; 2-glycol dimethyl ether or 1; 4-dioxane, or the various combination of above-mentioned solvent; Reaction is preferential to be selected to contain in the solvent of hydrogenchloride and carries out, like 1 of the tetrahydrofuran solution of the ethanolic soln of the methanol solution of hydrogenchloride, hydrogenchloride, hydrogenchloride, hydrogenchloride, 2-glycol dimethyl ether solution; In these solvents, remove the protection base; The product of gained is the hydrochloride form that needs, and because of the existence of hydrogenchloride, catalyzer is difficult for poisoning, active height; Reaction can occur between-10 ℃～solvent refluxing temperature, preferentially selects to carry out under the room temperature condition; Used hydrogen can be normal pressure or high pressure hydrogen, and pressure range is 0.1MPa～20MPa.
Figure BSA00000192183900021
Second purpose of the present invention provides compound I and preparation method thereof.Compound I can be through corresponding bisamide (Bis-amide) II, III or IV reduction preparation; Or by the reduction of monoamine-monoamide (amine-amide) V or VI preparation; The concrete structure of compound I I～compound VI is shown in Scheme 1, and wherein Ar and R are as previously mentioned.
Figure 201010227799X1000022
But reductive agents such as this reduction reaction aluminium hydrogen reagent, boron hydrogen reagent; The aluminium hydrogen reagent can be Lithium Aluminium Hydride, DIBAL, K-Selectride or L-Selectride, and the boron hydrogen reagent can be Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, cyanic acid POTASSIUM BOROHYDRIDE 97MIN, triethyl-boron potassium hydride KH, lithium triethylborohydride or borine; Reductive agent can with combinations such as protonic acid example hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, tosic acid, formic acid, acetate, trifluoroacetic acid, propionic acid or butyric acid; Or sour with Lewis like combinations such as zinc chloride, magnesium chloride, tetraisopropoxy titanium, titanium tetrachlorides, to improve reactive behavior, to guarantee to react and carry out smoothly; The used solvent of this reduction reaction can be selected the alcohols of 1～6 carbon such as the various combination of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol or these solvents; Perhaps ether property solvent such as ether, MTBE, Di Iso Propyl Ether, THF, 2-methyltetrahydrofuran, 1; 2-glycol dimethyl ether, 1, the various combination of 4-dioxane or these solvents; This reduction reaction can take place between-30 ℃～solvent refluxing temperature, specifically looks the active different and different of reductive agent.
The 3rd purpose of the present invention provides compound I I～compound VI and preparation method thereof.The raw material of the middle portion of compound I I～compound VI structure can derive from 6-aminocaprolc acid, 6-caprolactone or 1,6-hexanodioic acid, or their chemical equivalence body; Two side portions raw material in the structure can come from toluylic acid, phenylethylamine, 3,4-two arylmethyl toluylic acids or 3,4-two arylmethyl phenylethylamines, or their chemical equivalence body.Different according to the raw material selected for use, can prepare compound I I～compound VI via different synthetic routes, the condensation reaction that reaction type mainly contains into acid amides becomes two types of the substitution reactions of secondary amine with primary amine.
Wherein, condensation reaction can carboxylic acid and the direct condensation method of amine, the carboxylic acid halides method of carboxylic acid or the active ester method of carboxylic acid.
Directly the condensing agent of condensation method can be selected DCC, EDCI, CDI, HATU, HBTU, HOAt, HOBt, chloro-formic ester for use; Solvent can be selected methylene dichloride, ethylene dichloride, THF, 2-methyltetrahydrofuran, N for use, dinethylformamide, DMAC N,N, hexanaphthene, or the multiple combination of above-mentioned solvent; React used alkali and can be organic bases such as Dimethylamino pyridine, triethylamine, diisopropyl ethyl amine, N, accelerine or pyridine also can be mineral alkali such as soda ash light, Anhydrous potassium carbonate; The temperature of this reaction can be-30 a ℃～solvent refluxing temperature, preferred 0 ℃～40 ℃.
The carboxylic acid halides method can be selected acylating reagents such as acyl chlorides, acylbromide for use; Solvent can be selected methylene dichloride, ethylene dichloride, THF, 2-methyltetrahydrofuran, N for use; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, hexanaphthene, ETHYLE ACETATE, benzene,toluene,xylene, acetonitrile, acetone, butanone, 1, the 4-dioxane, or above-mentioned solvent in the mixed liquid of one or more and water; The used alkali of this reaction can be mineral alkali or organic bases; Mineral alkali can be selected sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood for use; Organic bases can be selected triethylamine, Dimethylamino pyridine, diisopropyl ethyl amine, Trimethylamine 99, N for use, accelerine or pyridine; The temperature of this reaction can be-30 a ℃～solvent refluxing temperature.
Active ester method can be the active ester that NHS, Suf-NHS, HOBt or HOAt and respective acids form; Solvent can be selected methylene dichloride, ethylene dichloride, THF, 2-methyltetrahydrofuran, N for use; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, hexanaphthene, ETHYLE ACETATE, benzene,toluene,xylene, acetonitrile, acetone, butanone, 1, the 4-dioxane, or above-mentioned solvent in the mixed liquid of one or more and water; The used alkali of this reaction can be mineral alkali or organic bases; Mineral alkali can be selected sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood for use; Organic bases can be selected triethylamine, Dimethylamino pyridine, diisopropyl ethyl amine, Trimethylamine 99, N for use, accelerine or pyridine; The temperature of this reaction can be-30～solvent refluxing temperature.
Substitution reaction is that corresponding alcohol is prepared into its halohydrocarbon or plan halohydrocarbon, with primary amine back preparation secondary amine midbody takes place to replace again; Its halohydrocarbon can be chlorine, bromine or idohydrocarbon, and intending halohydrocarbon can be its methanesulfonates, p-toluenesulfonic esters, benzene sulfonate; Solvent can be selected methylene dichloride, ethylene dichloride, THF, 2-methyltetrahydrofuran, N for use; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, hexanaphthene, methyl acetate, ETHYLE ACETATE, benzene,toluene,xylene, acetonitrile, acetone, butanone, 1, the various combination of 4-dioxane, Virahol or above-mentioned solvent; The used alkali of this reaction can be mineral alkali or organic bases; Mineral alkali can be selected sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood for use; Organic bases can be selected triethylamine, Trimethylamine 99, diisopropyl ethyl amine, Dimethylamino pyridine, N for use, accelerine or pyridine; The temperature of this reaction can be-10 a ℃～solvent refluxing temperature.
In a word; Existing FPL-60278AR synthetic route all adopts the methyl guard method; The later stage demethylation protection base of operational path need can be accomplished under the hydrobromic acid solution medium and high temperature in long-time reaction; Byproduct of reaction is many, and the Hydrogen bromide dopexamine of gained need be converted into the hydrochloride of dopexamine again.The present invention is directed to this deficiency, utilize arylmethyl protection 1 first, 2-dihydroxy-benzene strategy has been accomplished the new study on the synthesis of FPL-60278AR smoothly.In the later stage of route of the present invention, utilize transition metal-catalyzed hydrogenation to remove the corresponding protection base of dopexamine hydrochloride of resulting pair of arylmethyl protection, can obtain FPL-60278AR.
If simple benzyl (Ar is that phenyl and R the are hydrogen) protection of the arylmethyl among the present invention base, deprotection reaction can be accomplished in room temperature, palladium charcoal catalytic hydrogenation smoothly, gentle easy control; No coupling product produces, and this step reaction yield is almost quantitative, and reaction is as if methyl alcohol, ethanol, THF or 1 at hydrogenchloride; Carry out in the 2-glycol dimethyl ether, can reduce poisoning of catalyst, improve its catalytic activity; And directly obtain its hydrochloride medicinal forms, more simple and direct.
Embodiment
Following practical implementation instance is for the present invention more completely is described, and does not mean that restriction is like defined scope of the present invention in the claim by any way.
The preparation of 6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) amino-N-(2-styroyl) hexanamide (2)
The preparation of embodiment 1:6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) hexosamine (8)
In below 10 ℃, with Et 3N 24.4mL (175mmol) slowly drips to 6-aminocaprolc acid 18.3g (140mmol), H 2In the mixed liquid of O150mL and MeCN 50mL, the limit edged stirs.After treating stirring and dissolving, more slowly with N-hydroxy-succinamide 3, the acetonitrile 100mL drips of solution of 4-benzyloxy phenylacetate 31.2g (70mmol) is added in this mixed liquid.Drip and finish, rise to room temperature naturally, continue to stir 3h, the TLC detection reaction finishes basically.Concentrating under reduced pressure is removed most of solvent, and resistates inclines to the mixed liquid of ETHYLE ACETATE 200mL and frozen water 200mL, transfers pH 2～3 with Hydrogen chloride; Obtain organic layer; Water layer merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying with ETHYLE ACETATE (50mL * 2) extraction.Filter, concentrate, faint yellow solid 29.8g, yield is 92.3%, m.p.108～110 ℃.
MS(m/z)：[M+H] +462.1，[M+Na] +489.1，[M+K] +499.8。
The preparation of embodiment 2:6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) hexosamine (8)
In below 10 ℃, with Et 3N 24.4mL (175mmol) slowly drips to 6-aminocaprolc acid 18.3g (140mmol), hexanaphthene 150mL and H 2In the mixed liquid of O 250mL, the limit edged stirs.After waiting to dissolve, more slowly with 3, the hexanaphthene 100mL drips of solution of 4-benzyloxy phenyllacetyl chloride 25.7g (70mmol) is added in this reaction system.Drip and finish, rise to room temperature naturally, continue to stir 3h, the TLC detection reaction finishes basically.Transfer pH 2～3 with Hydrogen chloride, obtain organic layer, water layer merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying with hexanaphthene (50mL * 2) extraction.Filter, the organic layer concentrating under reduced pressure gets faint yellow solid 27.6g, and yield is 85.5%.
The preparation of embodiment 3:6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) amino-N-(2-styroyl) hexanamide (2)
In room temperature, CDI 5.8g (27.0mmol) is added to the CH of 6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) hexosamine (8) 8.3g (18.0mmol) 2Cl 2In the 200mL solution, behind the stirring 2h, add 2-phenylethylamine 4.5mL (27.0mmol) again, continue to stir 5h, the TLC detection reaction finishes basically.Reaction solution is inclined to frozen water 300mL, obtain organic layer, water layer is with CH 2Cl 2(50mL * 2) extraction merges organic phase, and water (100mL * 2) is washed anhydrous sodium sulfate drying.Filter, concentrate, obtain white solid 8.8g, yield is 86.3%.
MS(m/z)：[M+H] +565.3，[M+Na] +587.3，[M-H] -563.1，[M+Cl] -599.1。
1H?NMR(CDCl 3，600MHz)δ＝1.19～1.21(2H，m)，1.36～1.38(2H，m)，1.54～1.56(2H，m)，2.06(2H，t)，2.78(2H，t)，3.12～3.14(2H，dd)，3.44(2H，s)，3.47～3.49(2H，dd)，5.14(4H，s)，5.39(2H，br，d)，6.74～6.91(3H，m)，7.16～7.43(15H，m).
The preparation of embodiment 4:6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) amino-N-(2-styroyl) hexanamide (2)
In below 5 ℃, DCC 17.3g (24.0mmol), DMAP 0.4g (3.5mmol) are added to 6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) hexosamine (9) 9.2g (20.0mmol), N-hydroxy-succinamide (NHS) 2.8g (24.0mmol) and anhydrous CH successively 2Cl 2In the mixed liquid of 200mL.Finish, rise to room temperature naturally, stirred overnight, the TLC detection reaction finishes basically.Filter, mother liquor is concentrated into about 50mL.
In below 10 ℃, above-mentioned solution is slowly dripped to 2-phenylethylamine 6.7mL (40mmol) and CH 2Cl 2In the solution of 50mL, the limit edged stirs.Drip and finish, rise to room temperature naturally, continue to stir 3h, the TLC detection reaction finishes basically.Transfer pH 3～4 with Hydrogen chloride, obtain organic layer, water layer is with CH 2Cl 2(50mL * 2) extraction merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying.Filter, the organic layer concentrating under reduced pressure gets faint yellow solid 9.8g, and yield is 86.7%.
The preparation of N-(2-(3, the 4-benzyloxy phenenyl) ethyl)-6-(2-phenylacetylamino) hexanamide (3)
The preparation of embodiment 5:6-(2-phenylacetylamino) caproic acid (10)
In below 10 ℃, with Et 3N 34.9mL (0.25mol) slowly drips to 6-aminocaprolc acid 26.2g (0.20mol), hexanaphthene 100mL and H 2In the mixed liquid of O 200mL, the limit edged stirs.After waiting to dissolve, the 50mL cyclohexane solution with phenyllacetyl chloride 15.5g (0.10mol) slowly drips to this reaction system again.Drip and finish, rise to room temperature naturally, continue to stir 3h, the TLC detection reaction finishes basically.Transfer pH 2～3 with Hydrogen chloride, obtain organic layer, water layer merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying with hexanaphthene (50mL * 2) extraction.Filter, concentrate, faint yellow solid 20.6g, yield is 82.7%, m.p.77～79 ℃.
MS(m/z)：[M+H] +249.9，[M+Na] +271.8，[M-H] -248.1。
1H?NMR(CDCl 3，300MHz)δ＝1.25～1.33(2H，m)，1.39～1.49(2H，m)，1.55～1.65(2H，m)，2.31(2H，t)，3.18～3.23(2H，dd)，3.58(2H，s)，5.44(1H，br，s)，7.24～7.38(5H，m)。
The preparation of embodiment 6:6-(2-phenylacetylamino) caproic acid (10)
In below 10 ℃, with Et 3N 34.9mL (0.25mol) slowly drips to 6-aminocaprolc acid 26.2g (0.20mol), MeCN 50mL and H 2In the mixed liquid of O 200mL, the limit edged stirs.After treating stirring and dissolving, the acetonitrile 150mL solution with N-hydroxy-succinamide phenylacetate 23.3g (0.10mol) slowly drips to this reaction system again.Drip and finish, rise to room temperature naturally, continue to stir 3h, the TLC detection reaction finishes basically.Concentrating under reduced pressure is removed most of solvent, and resistates is inclined to the mixed liquid of ETHYLE ACETATE 200mL and frozen water 200mL, transfers pH 2～3 with Hydrogen chloride; Obtain organic layer; Water layer merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying with ETHYLE ACETATE (50mL * 2) extraction.Filter, concentrate, get faint yellow solid 21.2g, yield is 85.1%.
The preparation of embodiment 7:N-(2-(3, the 4-benzyloxy phenenyl) ethyl)-6-(2-phenylacetylamino) hexanamide (3)
In room temperature, CDI 1.95g (12.0mmol) is added to the 50mLCH of 6-(2-phenylacetylamino) caproic acid (10) 2.0g (8.0mmol) 2Cl 2In the solution, stir 2h.2-(3, the 4-benzyloxy phenenyl) ethamine (11) 2.8g (8.0mmol) is added in this reaction system again, continue to stir 10h, the TLC detection reaction finishes basically.Reaction solution is inclined to frozen water 100mL, obtain organic layer, water layer is with CH 2Cl 2(20mL * 2) extraction merges organic phase and water (50mL * 2) and washes anhydrous sodium sulfate drying.Filter, concentrate, obtain white solid 3.84g, yield is 81.9%.
1H?NMR(CDCl 3，300MHz)δ＝1.18～1.26(2H，m)，1.38～1.43(2H，m)，1.52～1.57(2H，m)，2.04(2H，t)，2.69(2H，t)，3.15～3.19(2H，dd)，3.40～3.44(2H，dd)，3.53(2H，s)，5.13(4H，s)，5.50(2H，br，d)，6.70～6.89(3H，m)，7.24～7.45(15H，m).
N 1-(2-(3, the 4-benzyloxy phenenyl) ethyl)-N 6-(2-styroyl)-1, the preparation of 6-adipamide (4)
Embodiment 8: in below 5 ℃; DCC 5.2g (25.0mol) and DMAP 0.2g are added to N-(2-styroyl) hexanodioic acid monoamide 6.0g (24.0mmol) (12), 2-(3 successively; The 4-benzyloxy phenenyl) in the mixed liquid of ethamine (11) 8.0g (24.0mmol) and THF 50mL; Naturally rise to ambient temperature overnight, the TLC detection reaction finishes basically.Filter, mother liquor concentrates and reclaims THF, and resistates is with CH 2Cl 2The 100mL dissolving is inclined to frozen water 100mL, obtains organic layer, and water layer is with CH 2Cl 2(20mL * 2) extraction merges organic layer and water (50mL * 2) and washes anhydrous sodium sulfate drying.Filter, concentrate, obtain white solid 11.7g, yield is 86.0%.
MS(m/z)：[M+H] +565.3，[M+Na] +587.3，[M-H] -563.1。
Embodiment 9: in below 5 ℃; DCC 6.8g (33.0mol) and DMAP 0.2g are added to N-successively, and (2-(3; The 4-benzyloxy phenenyl) ethyl) in the mixed liquid of hexanodioic acid monoamide (13) 13.8g (30.0mol), 2-phenylethylamine 5.0mL (30.0mol) and THF 100mL; Naturally rise to ambient temperature overnight, the TLC detection reaction finishes basically.Filter, mother liquor concentrates and reclaims THF, and resistates is with CH 2Cl 2The 100mL dissolving is inclined to frozen water 100mL, obtains organic layer, and water layer is with CH 2Cl 2(20mL * 2) extraction merges organic phase and water (50mL * 2) and washes anhydrous sodium sulfate drying.Filter, concentrate, obtain white solid 14.0g, yield is 82.8%.
The preparation of 6-(2-(3, the 4-benzyloxy phenenyl) ethyl) amino-N-(2-styroyl) hexanamide (5)
The preparation of embodiment 10:6-hydroxy-n-(2-styroyl) hexanamide (14)
With the mixed liquid back flow reaction 24h of 6-caprolactone 11.1mL (0.10mol), 2-phenylethylamine 15.1mL (0.12mol) and toluene 60mL, the TLC detection reaction finishes basically.Concentrating under reduced pressure reclaims toluene, and resistates to frozen water 150mL, is obtained organic phase with ETHYLE ACETATE 150mL dissolving hypsokinesis, and water layer merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying with ETHYLE ACETATE (40mL * 2) extraction.Filter, concentrate, get faint yellow oily thing 20.3g, yield is 87.1%.
The preparation of embodiment 11:6-oxo-6-(2-styroyl) amino-hexanol methanesulfonates (15)
In below 10 ℃, with Et 3N 5.0mL (36.0mmol) slowly is added to 6-hydroxy-n-(2-styroyl) hexanamide (14) 7.2g (30.0mmol) and CH 2Cl 2In the solution of 50mL, the limit edged stirs.Again with methylsulfonyl chloride 2.8mL (36.0mmol) and CH 2Cl 2The solution of 10mL slowly drips to this reaction system.Drip and finish, rise to room temperature naturally, continue reaction 2h, the TLC detection reaction finishes basically.Reaction solution is inclined to CH 2Cl 2In the mixed liquid of 50mL and water 100mL, obtain organic layer, water layer is with CH 2Cl 2(40mL * 2) extraction merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying.Filter, concentrate, obtain faint yellow solid 6.6g, yield is 70.5%.
MS(m/z)：[M+H] +314.0，[M+Na] +336.0。
The preparation of embodiment 12:6-(2-(3, the 4-benzyloxy phenenyl) ethyl) amino-N-(2-styroyl) hexanamide (5)
Stir down; Powdered Anhydrous potassium carbonate 5.5g (40.0mmol) is added in the mixed liquid of 6-oxo-6-(2-styroyl) amino-hexanol methanesulfonates (15) 9.4g (30.0mmol), 2-(3, the 4-benzyloxy phenenyl) ethamine (11) 6.7g (20.0mmol) and Virahol 100mL.Back flow reaction 24h, TLC detect also has the part material residue.Filter, mother liquor inclines to ETHYLE ACETATE 100mL and water 200mL, obtains organic layer, and water layer merges organic phase with ETHYLE ACETATE (50mL * 2) extraction, and water (100mL * 2) is washed anhydrous sodium sulfate drying.Filter, concentrate, column chromatography gets the 3.4g white solid, and yield is 30.9%.
MS(m/z)：[M+H] +551.5。
The preparation of N-(2-(3, the 4-benzyloxy phenenyl) ethyl)-6-(2-styroyl) aminocaproamide (6)
The preparation of embodiment 13:6-hydroxy-n-(2-(3, the 4-benzyloxy phenenyl) ethyl) hexanamide (16)
With the mixed liquid back flow reaction 24h of 6-caprolactone 13.3mL (0.12mol), 2-(3, the 4-benzyloxy phenenyl) ethamine (11) 33.3g (0.10mol) and toluene 200mL, the TLC detection reaction finishes basically.Concentrating under reduced pressure reclaims toluene, and resistates to water 200mL, is obtained organic layer with ETHYLE ACETATE 200mL dissolving hypsokinesis, and water layer merges organic phase and water (100mL * 2) and washes anhydrous sodium sulfate drying with ETHYLE ACETATE (50mL * 2) extraction.Filter, concentrate, get faint yellow oily thing 35.7g, yield is 79.7%.
The preparation of embodiment 14:6-oxo-6-(2-(3, the 4-benzyloxy phenenyl) ethyl) amino-hexanol methanesulfonates (17)
In below 10 ℃, with Et 3N 5.0mL (36.0mmol) slowly is added to 6-hydroxy-n-(2-(3, the 4-benzyloxy phenenyl) ethyl) hexanamide (16) 13.4g (30.0mmol) and CH 2Cl 2In the solution of 50mL, the limit edged stirs.Again with methylsulfonyl chloride 2.8mL (36.0mmol) and CH 2Cl 2The solution of 10mL slowly drips to this reaction system.Drip and finish, rise to room temperature naturally, continue reaction 2h, the TLC detection reaction finishes basically.Reaction solution is inclined to CH 2Cl 2Among 50mL and the water 100mL, obtain organic layer, water layer is with CH 2Cl 2(40mL * 2) extraction merges organic phase, and water (100mL * 2) is washed anhydrous sodium sulfate drying.Filter, concentrate, obtain faint yellow solid 11.4g, yield is 72.2%.
MS(m/z)：[M+H] +314.0，[M+Na] +336.0。
The preparation of embodiment 15:6-(2-styroyl) amino-N-(2-(3, the 4-benzyloxy phenenyl) ethyl) hexanamide (6)
Stir down; Powdered Anhydrous potassium carbonate 5.5g (40.0mmol) is added to 6-oxo-6-, and (2-(3; The 4-benzyloxy phenenyl) ethyl) in the mixed liquid of amino-hexanol methanesulfonates (17) 10.5g (20.0mmol), 2-phenylethylamine 3.0mL (24.0mmol) and Virahol 100mL; Back flow reaction 24h, TLC detect also has the part material residue.Filter, mother liquor inclines to ETHYLE ACETATE 100mL and water 200mL, obtains organic phase, and water layer merges organic phase with ETHYLE ACETATE (50mL * 2) extraction, and water (100mL * 2) is washed, and anhydrous sodium sulfate drying concentrates, and column chromatography gets the 4.8g white solid, and yield is 43.6%.
MS(m/z)：[M+H] +551.5。
N 1-(2-(3, the 4-benzyloxy phenenyl) ethyl)-N 6-(2-styroyl)-1, the preparation of 6-hexanediamine dihydrochloride (7)
Embodiment 16: in below 10 ℃, with NaBH 45.7g (in the solution of 2-(3, the 4-benzyloxy phenenyl) ethyl-6-(2-phenylacetyl) aminocaproamide (3) 14.1g (25.0mmol) and THF 150mL, the limit edged stirs (150.0mmol) to add to N-.After being uniformly dispersed, AcOH 8.6mL (150.0mmol) is slowly dripped to this reaction system, controlled temperature is below 20 ℃ again.Drip and finish, slowly rise to backflow, reaction 12h, the TLC detection reaction finishes basically.Filter, mother liquor concentrates and reclaims THF, and resistates inclines to the mixed liquid of ETHYLE ACETATE 100mL and frozen water 200mL, obtains organic layer, and water layer merges organic phase and water (50mL * 2) and washes anhydrous sodium sulfate drying with ETHYLE ACETATE (50mL * 2) extraction.Filter, concentrate and obtain thick liquid, with the methanol solution salify of hydrogenchloride, suction filtration, filter cake is washed with cold MeOH (15mL * 2), obtains white solid 13.6g, yield 89.2%.
MS(m/z)：[M+H] +537.3。
1H?NMR(DMSO-δ 6，300MHz)δ＝1.34(4H，s)，1.63(4H，s)，2.86～3.23(12H，m)，5.11(4H，d)，6.76～7.02(3H，m)，7.26～7.47(15H，m)，8.90(4H，br).
Embodiment 17: with 6-(2-(3, the 4-benzyloxy phenenyl) ethanoyl) amino-N-(2-styroyl) hexanamide (2) 14.1g (25.0mmol) replacement N-(2-(3, the 4-benzyloxy phenenyl) ethyl)-6-(2-phenylacetyl) aminocaproamide (3), method is seen instance 16.Get the 14.0g white solid, yield 91.9%.
Embodiment 18: with N 1-(2-(3, the 4-benzyloxy phenenyl) ethyl)-N 6-(2-styroyl)-1,6-adipamide (4) 14.1g (25.0mmol) replaces N-(2-(3, the 4-benzyloxy phenenyl) ethyl)-6-(2-phenylacetyl) aminocaproamide (3), and method is seen instance 16.Get the 14.2g white solid, yield 93.2%.
Embodiment 19: in below 10 ℃, with NaBH 42.9g (75.0mmol) be added in the solution of 6-(2-(3, the 4-benzyloxy phenenyl) ethyl) amino-N-(2-styroyl) hexanamide (5) 13.8g (25.0mmol) and THF 150mL, the limit edged stirs.After being uniformly dispersed, AcOH 4.3mL (75.0mmol) is slowly dripped to this reaction system, controlled temperature is below 20 ℃ again.Drip and finish, slowly rise to backflow, reaction 12h, the TLC detection reaction finishes basically.Filter, mother liquor concentrates and reclaims THF, and resistates inclines to the mixed liquid of ETHYLE ACETATE 100mL and frozen water 200mL, obtains organic layer, and water layer merges organic phase with ETHYLE ACETATE (50mL * 2) extraction, and water (50mL * 2) is washed anhydrous sodium sulfate drying.Filter, concentrate and obtain thick liquid, with the methanol solution salify of hydrogenchloride, suction filtration, filter cake is washed with cold MeOH (15mL * 2), obtains white solid 12.1g, yield 79.4%.
Embodiment 20: with N-(2-(3, the 4-benzyloxy phenenyl) ethyl)-6-(2-styroyl) aminocaproamide (6) 13.8g (25.0mmol) replacement 6-(2-(3, the 4-benzyloxy phenenyl) ethyl) amino-N-(2-styroyl) hexanamide (5), method is seen instance 19.Get the 12.8g white solid, yield 84.0%.
The preparation of FPL-60278AR (1)
Embodiment 21: stir down, Pd/C (10%) 1.0g is added to N 1-(2-(3, the 4-benzyloxy phenenyl) ethyl)-N 6-(2-styroyl)-1 in the mixed liquid of 6-hexanediamine dihydrochloride (7) 10.0g and methyl alcohol 200mL, takes off benzyl in room temperature normal pressure catalytic hydrogenation, and the TLC detection reaction finishes basically behind the reaction 10h.Filtered and recycled Pd/C concentrates, and gets white solid 6.9g, yield 98.6%.With methyl alcohol 30mL recrystallization, activated carbon decolorizing 30 minutes, heat filtering, mother liquor is slowly lowered the temperature, and separates out white solid.Abundant cooling back suction filtration, filter cake is washed with methyl alcohol (5mL * 2), and 40～50 ℃ of drying under reduced pressure 2h are weighed as 5.8g, and yield is 87.1%, m.p.218～220 ℃.
MS(m/z)：[M+H] +?537.3。
1H?NMR(DMSO-δ 6，300MHz)δ＝1.32(4H，s)，1.62(4H，s)，2.74～3.15(12H，m)，6.45～6.68(3H，m)，7.21～7.25(15H，m)，8.84～8.90(2H，br，d)，8.96～9.10(2H，br，d)。
13C?NMR(DMSO-δ 6，75MHz)δ＝25.26，25.54，31.00，31.55，46.56，47.80，48.25，115.86，116.11，119.25，126.81，127.97，128.70，137.44，144.15，145.41。

Claims (16)

1.一种盐酸多培沙明的制备方法，其特征在于：通过对双芳甲基保护的盐酸多培沙明(I)进行催化氢化，选择性地脱除相应的芳甲基保护基，直接得到多培沙明的盐酸盐(1)。 1. a preparation method of dopexamine hydrochloride, is characterized in that: by carrying out catalytic hydrogenation to the dopexamine hydrochloride (I) of two arylmethyl protections, selectively removes corresponding arylmethyl protecting group, The hydrochloride salt (1) of dopexamine is obtained directly. 2.如权利要求1中所述的制备方法，其特征在于以过渡金属为催化剂，所用催化剂可为钯、钌、铑、或镍；为提高这些催化剂的催化活性，可将这些金属负载于载体上，载体可为活性炭、硅藻土、分子筛、氧化铝、或硅胶。 2. preparation method as described in claim 1, it is characterized in that with transition metal as catalyst, used catalyst can be palladium, ruthenium, rhodium or nickel; For improving the catalytic activity of these catalysts, these metals can be loaded on carrier The carrier can be activated carbon, diatomaceous earth, molecular sieves, alumina, or silica gel. 3.如权利要求1中所述的制备方法，其特征在于反应所用的溶剂可选择1～6个碳的醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、或叔丁醇，或者醚性溶剂如乙醚、甲基叔丁基醚、二异丙基醚、四氢呋喃、2-甲基四氢呋喃、1，2-二甲氧基乙烷、或1，4-二氧六环，或上述溶剂的不同组合。 3. preparation method as described in claim 1, it is characterized in that the used solvent of reaction can select the alcohols of 1～6 carbons such as methyl alcohol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , or tert-butanol, or ether solvents such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, or 1,4- Dioxane, or various combinations of the above solvents. 4.如权利要求1中所述的制备方法，其特征在于反应优先选择在含有氯化氢的溶剂中进行，如氯化氢的甲醇溶液、氯化氢的乙醇溶液、氯化氢的四氢呋喃溶液、氯化氢的1，2-二甲氧基乙烷溶液。 4. The preparation method as claimed in claim 1, characterized in that the reaction is preferably carried out in a solvent containing hydrogen chloride, such as the methanol solution of hydrogen chloride, the ethanol solution of hydrogen chloride, the tetrahydrofuran solution of hydrogen chloride, the 1,2-dihydrofuran solution of hydrogen chloride Methoxyethane solution. 5.如权利要求1中所述的制备方法，其特征在于反应可发生在-10℃～溶剂回流温度间，优先选择室温条件下进行；所用的氢气可为常压或高压氢气，压力范围为0.1MPa～20MPa。 5. The preparation method as claimed in claim 1, characterized in that the reaction can take place between -10°C and solvent reflux temperature, preferably at room temperature; the hydrogen used can be normal pressure or high pressure hydrogen, and the pressure range is 0.1MPa～20MPa. 6.如权利要求1中所述的式I，Ar可为：苯基，甲基取代的苯基，甲氧基取代的苯基，硝基取代的苯基，氟、氯、溴或碘取代的苯基，芳杂环如吡啶、噻吩、呋喃，1-萘基或2-萘基，甲基取代的1-萘基或2-萘基，硝基取代的1-萘基或2-萘基，氟、氯、溴或碘取代的1-萘基或2-萘基；R可为：氢、甲基或苯基；所述Ar优选为苯基及R优选为氢。 6. The formula I as claimed in claim 1, Ar can be: phenyl, methyl substituted phenyl, methoxy substituted phenyl, nitro substituted phenyl, fluorine, chlorine, bromine or iodine substitution phenyl, aromatic heterocycles such as pyridine, thiophene, furan, 1-naphthyl or 2-naphthyl, methyl-substituted 1-naphthyl or 2-naphthyl, nitro-substituted 1-naphthyl or 2-naphthyl Base, 1-naphthyl or 2-naphthyl substituted by fluorine, chlorine, bromine or iodine; R can be: hydrogen, methyl or phenyl; said Ar is preferably phenyl and R is preferably hydrogen. 7.化合物I可经相应的双酰胺(Bis-amide)II、III或IV还原制备，或由单胺-单酰胺(amine-amide)V或VI还原制备，化合物II～化合物VI的具体结构如Scheme 1所示，其中Ar和R如权利要求6所述。 7. Compound I can be prepared by reduction of corresponding bis-amide (Bis-amide) II, III or IV, or by reduction of monoamine-monoamide (amine-amide) V or VI. The specific structures of compound II～compound VI are as follows Shown in Scheme 1, wherein Ar and R are as described in claim 6. 8.如权利要求7中所述的制备方法，其特征在于还原剂可选用铝氢试剂、硼氢试剂等，铝氢试剂可为四氢铝锂、DIBAL、K-Selectride、或L-Selectride，硼氢试剂可为硼氢化钠、硼氢化钾、氰基硼氢化钾、三乙基硼氢化钾、三乙基硼氢化锂或硼烷；还原剂可与质子酸如盐酸、硫酸、磷酸、甲磺酸、三氟甲磺酸、樟脑磺酸、对甲苯磺酸、甲酸、乙酸、三氟乙酸、丙酸、或丁酸等组合，或与Lewis酸如氯化锌、氯化镁、四异丙氧基钛、四氯化钛等组合，以提高反应活性、确保反应顺利进行。 8. The preparation method as claimed in claim 7, characterized in that the reductant can be selected aluminum hydride reagent, boron hydride reagent, etc., and the aluminum hydride reagent can be lithium aluminum hydride, DIBAL, K-Selectride or L-Selectride, The borohydride reagent can be sodium borohydride, potassium borohydride, potassium cyanoborohydride, potassium triethylborohydride, lithium triethylborohydride or borane; Combinations of sulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, or butyric acid, or with Lewis acids such as zinc chloride, magnesium chloride, tetraisopropoxy Base titanium, titanium tetrachloride and other combinations to improve the reactivity and ensure the smooth progress of the reaction. 9.如权利要求7中所述的方法，其特征在于该还原反应所用的溶剂可选择1～6个碳的醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、或这些溶剂的不同组合，或者醚性溶剂如乙醚、甲基叔丁基醚、二异丙基醚、四氢呋喃、2-甲基四氢呋喃、1，2-二甲氧基 乙烷、1，4-二氧六环、或这些溶剂的不同组合。 9. The method as claimed in claim 7, characterized in that the used solvent of the reduction reaction can be selected from alcohols with 1 to 6 carbons such as methyl alcohol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol Alcohol, tert-butanol, or different combinations of these solvents, or ether solvents such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane alkanes, 1,4-dioxane, or various combinations of these solvents. 10.如权利要求7中所述的方法，其特征在于该还原反应可于-30℃～溶剂回流温度间发生。 10. The method as claimed in claim 7, wherein the reduction reaction can occur between -30°C and the reflux temperature of the solvent.
Figure 2
Figure 2
 11.化合物II～化合物VI结构的中间部分的原料可来源于6-氨基己酸、6-己内酯、或1，6-己二酸，或它们的化学等价体；结构中的两侧部分原料可来自于苯乙酸、苯乙胺、3，4-二芳甲基苯乙酸、或3，4-二芳甲基苯乙胺，或它们的化学等价体；根据选用的原料不同，可经由不同的合成路线来制备化合物II～化合物VI，反应类型主要有成酰胺的缩合反应和伯胺成仲胺的取代反应两种类型。 11. The raw materials of the middle part of the compound II～compound VI structure can be derived from 6-aminocaproic acid, 6-caprolactone, or 1,6-adipic acid, or their chemical equivalents; the two sides in the structure Some raw materials can come from phenylacetic acid, phenethylamine, 3,4-diarylmethylphenylacetic acid, or 3,4-diarylmethylphenylethylamine, or their chemical equivalents; according to the different raw materials selected, Compounds II to VI can be prepared through different synthetic routes, and the reaction types mainly include condensation reaction to form amides and substitution reaction from primary amines to secondary amines. 12.如权利要求11中所述的反应类型，其特征在于所述缩合反应可以为羧酸与胺的直接缩合法、羧酸的酰卤法、或羧酸的活泼酯法。 12. The reaction type as claimed in claim 11, characterized in that the condensation reaction can be the direct condensation method of carboxylic acid and amine, the acid halide method of carboxylic acid, or the active ester method of carboxylic acid. 13.如权利要求12中所述的制备方法，其特征在于直接缩合法的缩合剂可选用DCC、EDCI、CDI、HATU、HBTU、HOAt、HOBt、或氯甲酸酯；溶剂可选用二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、或环己烷，或上述溶剂的多种组合；反应所用的碱可为有机碱如二甲氨基吡啶、三乙胺、二异丙基乙基胺、N，N-二甲基苯胺、或吡啶，也可为无机碱如无水碳酸钠、无水碳酸钾；该反应的温度可以是-30℃～溶剂回流温度，优选0℃～40℃。 13. preparation method as described in claim 12 is characterized in that the condensing agent of direct condensation method can be selected DCC, EDCI, CDI, HATU, HBTU, HOAt, HOBt or chloroformate; Solvent can be selected dichloromethane , dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, or cyclohexane, or various combinations of the above solvents; the reaction used The base can be an organic base such as dimethylaminopyridine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, or pyridine, or an inorganic base such as anhydrous sodium carbonate, anhydrous potassium carbonate ; The reaction temperature can be -30 ° C ~ solvent reflux temperature, preferably 0 ° C ~ 40 ° C. 14.如权利要求12中所述的制备方法，其特征在于酰卤法可选用酰氯、酰溴等酰化试剂；溶剂可选用二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、环己烷、乙酸乙酯、苯、甲苯、二甲苯、乙腈、丙酮、丁酮、1，4-二氧六环、或者上述溶剂中的一种或多种与水的混和液；该反应所用的碱可为无机碱或有机碱，无机碱可选用氢氧化钠、氢氧化钾、氢氧化锂、碳酸氢钠、碳酸氢钾、碳酸钠、或碳酸钾，有机碱可选用三乙胺、二甲氨基吡啶、二异丙基乙基胺、三甲胺、N，N-二甲基苯胺、或吡啶；该反应的温度可以是-30℃～溶剂回流温度。 14. The preparation method as claimed in claim 12, characterized in that the acyl halide method can be selected from acylating reagents such as acyl chloride and acyl bromide; the solvent can be selected from methylene dichloride, ethylene dichloride, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, cyclohexane, ethyl acetate, benzene, toluene, xylene, acetonitrile, acetone, butanone, 1,4-dioxane , or a mixed solution of one or more of the above-mentioned solvents and water; the base used in this reaction can be an inorganic base or an organic base, and the inorganic base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, Potassium bicarbonate, sodium carbonate or salt of wormwood, organic base can be selected triethylamine, dimethylaminopyridine, diisopropyl ethylamine, trimethylamine, N, N-dimethylaniline or pyridine; The reaction The temperature may be -30°C to solvent reflux temperature. 15.如权利要求12中所述的制备方法，其特征在于活泼酯法可以选用NHS、Sulfo-NHS、 HOBt、或HOAt与相应酸形成的活泼酯；溶剂可选用二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、环己烷、乙酸乙酯、苯、甲苯、二甲苯、乙腈、丙酮、丁酮、1，4-二氧六环、或者上述溶剂中的一种或多种与水的混和液；该反应所用的碱可以是无机碱或是有机碱，无机碱可以选用氢氧化钠、氢氧化钾、氢氧化锂、碳酸氢钠、碳酸氢钾、碳酸钠、或碳酸钾，有机碱可以选用三乙胺、二甲氨基吡啶、二异丙基乙基胺、三甲胺、N，N-二甲基苯胺、或吡啶；该反应的温度可以是-30℃～溶剂回流温度。 15. preparation method as described in claim 12 is characterized in that active ester method can select the active ester that NHS, Sulfo-NHS, HOBt or HOAt and corresponding acid form for use; Solvent can select dichloromethane, ethylene dichloride for use , tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, cyclohexane, ethyl acetate, benzene, toluene, xylene, acetonitrile, acetone, butanone , 1,4-dioxane, or a mixed solution of one or more of the above-mentioned solvents and water; the alkali used in this reaction can be an inorganic base or an organic base, and the inorganic base can be selected from sodium hydroxide, hydroxide Potassium, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, the organic base can be triethylamine, dimethylaminopyridine, diisopropylethylamine, trimethylamine, N, N-di Methylaniline, or pyridine; the reaction temperature can be -30°C~solvent reflux temperature. 16.如权利要求11中所述的反应类型，其特征在于所述取代反应是将相应的醇制备成其卤代烃或拟卤代烃、再与伯胺发生取代后制备仲胺中间体，其卤代烃可以是氯、溴、或碘代烃，拟卤代烃可以是其甲磺酸酯、对甲苯磺酸酯、苯磺酸酯；溶剂可以选用二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、环己烷、乙酸甲酯、乙酸乙酯、苯、甲苯、二甲苯、乙腈、丙酮、丁酮、1，4-二氧六环、异丙醇、或上述溶剂的不同组合；该反应所用的碱可以是无机碱或是有机碱，无机碱可以选用氢氧化钠、氢氧化钾、氢氧化锂、碳酸氢钠、碳酸氢钾、碳酸钠、或碳酸钾，有机碱可以选用三乙胺、三甲胺、二异丙基乙基胺、二甲氨基吡啶、N，N-二甲基苯胺、或吡啶；该反应的温度可以是-10℃～溶剂回流温度。  16. The reaction type as claimed in claim 11, characterized in that the substitution reaction is to prepare the corresponding alcohol into its halogenated hydrocarbon or pseudo-halogenated hydrocarbon, then substitute with the primary amine to prepare the secondary amine intermediate, Its halogenated hydrocarbon can be chlorine, bromine, or iodohydrocarbon, and pseudohalogenated hydrocarbon can be its mesylate, p-toluenesulfonate, benzenesulfonate; Solvent can be selected dichloromethane, dichloroethane, Tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, cyclohexane, methyl acetate, ethyl acetate, benzene, toluene, xylene, acetonitrile, acetone , butanone, 1,4-dioxane, isopropanol, or different combinations of the above-mentioned solvents; the base used in this reaction can be an inorganic base or an organic base, and the inorganic base can be selected from sodium hydroxide, potassium hydroxide, Lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, the organic base can be triethylamine, trimethylamine, diisopropylethylamine, dimethylaminopyridine, N,N-dimethyl Aniline, or pyridine; the temperature of the reaction can be -10°C~solvent reflux temperature. the
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435430A (en) * 2013-08-08 2013-12-11 四川大学 Method for reducing amide compounds
CN105001103A (en) * 2015-05-31 2015-10-28 江苏同禾药业有限公司 Method for synthesizing Dopexamino intermediate
CN105272861A (en) * 2015-11-16 2016-01-27 沈阳双鼎制药有限公司 Dopexamine hydrochloride and novel preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0117033A2 (en) * 1983-01-21 1984-08-29 FISONS plc Pharmaceutical formulations
EP0901458B1 (en) * 1996-05-22 2000-12-20 Bayer Ag Process for preparing 4,6-diamino-resorcinol-dihydrochloride
CN1901916A (en) * 2003-11-19 2007-01-24 希龙公司 Quinazolinone compounds with reduced bioaccumulation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0117033A2 (en) * 1983-01-21 1984-08-29 FISONS plc Pharmaceutical formulations
EP0901458B1 (en) * 1996-05-22 2000-12-20 Bayer Ag Process for preparing 4,6-diamino-resorcinol-dihydrochloride
CN1901916A (en) * 2003-11-19 2007-01-24 希龙公司 Quinazolinone compounds with reduced bioaccumulation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ROE ET等: "Chemistry of epoxy compounds :EPoxidation of oleamide and N-substituted oleamides with peracetie acid", 《JOURNAL OF AMERICAN SOCIETY》 *
芦金荣等: "多培沙明的合成", 《中国药科大学学报》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435430A (en) * 2013-08-08 2013-12-11 四川大学 Method for reducing amide compounds
CN105001103A (en) * 2015-05-31 2015-10-28 江苏同禾药业有限公司 Method for synthesizing Dopexamino intermediate
CN105272861A (en) * 2015-11-16 2016-01-27 沈阳双鼎制药有限公司 Dopexamine hydrochloride and novel preparation method thereof

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