CN102336676A - New preparation method of dopexamine hydrochloride by ArCHR protection strategy - Google Patents
New preparation method of dopexamine hydrochloride by ArCHR protection strategy Download PDFInfo
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Abstract
Belonging to the pharmaceutical field, the invention relates to a new preparation method of dopexamine hydrochloride (1), and dopexamine hydrochloride (I) protected by bis-ArCHR and a preparation method thereof. Utilizing an ArCHR protection strategy, the invention first prepares dopexamine hydrochloride (I) protected by bis-ArCHR, and then by making use of catalytic hydrogenation, removing corresponding ArCHR protective groups selectively, thus obtaining dopexamine hydrochloride.
Description
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
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.
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.
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. the preparation method of a FPL-60278AR is characterized in that: the FPL-60278AR (I) through to two arylmethyls protections carries out catalytic hydrogenation, optionally removes corresponding arylmethyl protection base, directly obtains the hydrochloride (1) of dopexamine.
2. the preparation method described in claim 1 is characterized in that with the transition metal being catalyzer, and catalyst system therefor can be palladium, ruthenium, rhodium or nickel; 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.
3. the preparation method described in claim 1; It is characterized in that the solvent that reacts used can select 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.
4. the preparation method described in claim 1; It is characterized in that reacting preferentially being chosen in the solvent that contains hydrogenchloride and carry 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.
5. the preparation method described in claim 1 is characterized in that 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.
6. the formula I described in claim 1, 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; Virtue 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.
7. compound I can be through corresponding bisamide (Bis-amide) II, III or IV reduction preparation; Or by monoamine-monoamide (amine-amide) V or VI reduction preparation; The concrete structure of compound I I～compound VI is shown in Scheme 1, and wherein Ar and R such as claim 6 are said.
8. the preparation method described in claim 7; But it is characterized in that reductive agent aluminium hydrogen reagent, boron hydrogen reagent etc.; 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.
9. the method described in claim 7; It is characterized in that the used solvent of this reduction reaction can select 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.
10. the method described in claim 7 is characterized in that this reduction reaction can take place between-30 ℃～solvent refluxing temperature.
11. 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.
12. the reaction type described in claim 11 is characterized in that said condensation reaction can be the direct condensation method of carboxylic acid and amine, the carboxylic acid halides method of carboxylic acid or the active ester method of carboxylic acid.
13. the preparation method 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 chloro-formic ester for use; Solvent can be selected methylene dichloride, ethylene dichloride, THF, 2-methyltetrahydrofuran, N for use, dinethylformamide, DMAC N,N or 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 ℃.
14. the preparation method described in claim 12 is characterized in that the carboxylic acid halides method can select 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.
15. the preparation method described in claim 12 is characterized in that the active ester that active ester method can select for use NHS, Sulfo-NHS, HOBt or HOAt and respective acids to 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 a ℃～solvent refluxing temperature.
16. the reaction type described in claim 11; It is characterized in that said 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.
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| 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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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