CN114591273B - Synthesis method and application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate - Google Patents

Synthesis method and application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate Download PDF

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CN114591273B
CN114591273B CN202210334941.3A CN202210334941A CN114591273B CN 114591273 B CN114591273 B CN 114591273B CN 202210334941 A CN202210334941 A CN 202210334941A CN 114591273 B CN114591273 B CN 114591273B
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tetrahydrofuranyl
propylenediamine
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oxalate
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CN114591273A (en
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孙丽梦
杨蓓蓓
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Bonentai Shandong Biomedical Technology Group Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention discloses a synthesis method and application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate, which react according to the following reaction formula to obtain a compound shown in a formula II:wherein A is N or C; x is halogen; r' is H or R, R is an amino protecting group; in the reaction process, ligand, catalyst and alkali are added into the reaction system to perform catalytic reaction according to the situation.

Description

Synthesis method and application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a synthesis method and application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
N-methyl-N' -tetrahydrofuranyl propylenediamine is an important intermediate compound for preparing alfuzosin and isoquinoline medicines, and the purity of raw materials directly influences the purity of products. However, the raw materials prepared by the preparation method in the prior art are generally oily, and have the following disadvantages: 1) The compound is oily and is easy to wrap the solvent, so that the solvent is difficult to remove, and solvent residues are more difficult to remove particularly in the process of scale-up production; 2) When the compound is oily, the material cannot be purified by adopting a conventional crystallization mode, and only the material can be purified by adopting a distillation mode, but the distillation and purification have the problems that only impurities with larger boiling points can be removed, and the impurities with smaller boiling points have no removal effect or poor removal effect, so that the oily material contains more impurities and has lower purity, the impurities can participate in subsequent reactions, new impurities are generated, and the purity of the final product is influenced.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a synthesis method and application of N-methyl-N' -tetrahydrofuranyl propane diamine oxalate.
In order to achieve the above object, the present invention is realized by the following technical scheme:
in a first aspect, the present invention provides a method for synthesizing N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate, comprising the steps of:
adding concentrated sulfuric acid into a mixed solution of methanol and 2-tetrahydrofuranic acid at low temperature, and heating for esterification reaction;
after the reaction is finished, cooling the reaction liquid, adding N-methyl-1, 3-propyldiamine, and heating for reaction; after the reaction is finished, removing methanol under reduced pressure, and adding isopropanol to carry methanol to obtain N-methyl-N' -tetrahydrofuranyl propylenediamine;
adding oxalic acid or hydrate thereof into the N-methyl-N '-tetrahydrofuranyl propylenediamine solution to react to obtain the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate.
In a second aspect, the invention provides application of the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate in preparing alfuzosin or isoquinoline drugs.
In a third aspect, the present invention provides a method for preparing alfuzosin or isoquinoline using N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate, wherein the method comprises the following steps:
wherein A is N or C; x is halogen; r' is H or R, R is an amino protecting group;
in the reaction process, ligand, catalyst and/or alkali are/is added into the reaction system to carry out catalytic reaction according to the situation.
The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:
the N-methyl-N' -tetrahydrofuranyl propylenediamine is prepared into oxalate, the oxalate product can be separated out to form solid, and has higher purity, and when the solid salt with higher purity is adopted to prepare alfuzosin or isoquinoline medicines, the obtained product has the advantages of high purity, high yield and the like.
N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate is difficult to Gao Wenjiang to be decomposed and has stronger high-temperature stability. Has no special requirement on storage conditions, and is easy to transport and sell.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a GC diagram of N-methyl-N' -tetrahydrofuranyl propylenediamine in example 1 of the present invention;
FIG. 2 is a GC diagram of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate prepared in example 1 according to the present invention;
FIG. 3 is an HPLC chart of Compound 12 prepared in example 2 of the present invention;
FIG. 4 is an HPLC chart of Compound 13 prepared in example 2 of the present invention;
FIG. 5 is an HPLC chart of compound 15 prepared in comparative example 3 of the present invention;
FIG. 6 is an HPLC chart of Compound 16 produced in comparative example 3 of the present invention.
FIG. 7 is an HPLC chart of Compound 12 prepared in comparative example 1 of the present invention;
FIG. 8 is an HPLC chart of Compound 13 prepared in comparative example 1 of the present invention;
FIG. 9 is an HPLC chart of compound 15 prepared in comparative example 1 of the present invention;
FIG. 10 is an HPLC chart of Compound 16 produced in comparative example 1 of the present invention.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The inventors used N-methyl-N '-tetrahydrofuranyl propylenediamine in the preparation of alfuzosin or isoquinoline drugs, and the synthetic route of the N-methyl-N' -tetrahydrofuranyl propylenediamine is shown as follows:
however, N-methyl-N' -tetrahydrofuranyl propylenediamine (Compound 3) is an oil, and the oily compound has the following disadvantages: first: the compound is oily and is easy to wrap the solvent, so that the solvent is difficult to remove. Especially in the scale-up production process, the solvent residues are more difficult to remove. The inventors tried to prepare N-methyl-N' -tetrahydrofuranyl propylenediamine by the above route, and the solvent residue in the prepared product is shown in Table 1:
TABLE 1
Batch of Starting materials Product yield Theoretical yield Molar yield Theoretical solvent residue
1 1.58kg 3.3kg 2.53kg 130％ 30％
2 22.0kg 49.8kg 35.3kg 141％ 41％
Second,: the material is oily, the material cannot be purified by adopting a conventional crystallization mode, and only the material can be purified by adopting a distillation mode, but the problem of pure distillation and purification is that only impurities with larger boiling point difference can be removed, and no removal effect or no obvious removal effect is achieved on the impurities with smaller boiling point difference, so that the oily material contains more impurities, and the purity can only reach about 90%.
When the oily raw material N-methyl-N' -tetrahydrofuranyl propylenediamine (compound 3) contains a large amount of solvent, the purity and yield of the alfuzosin or isoquinoline drugs are affected finally. In addition, the following two impurities are easy to exist in the preparation process of the N-methyl-N' -tetrahydrofuranyl propylenediamine.
The two impurities (the compound 4 and the compound 5) can participate in subsequent reactions, and the generated impurities can remain in the alfuzosin or isoquinoline medicines and are difficult to remove. Examples of side reactions involving the above two impurities are as follows:
1) The side reaction of the compound 4 impurity in isoquinoline drugs is as follows:
2) Side reactions of compound 5 in isoquinoline class drugs are as follows:
therefore, in order to solve the problems, the preparation of the N-methyl-N '-tetrahydrofuranyl propylenediamine into oxalate is attempted, the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate after salification is directly separated out from a reaction solution, impurities remain in a mother solution, and the impurities can be removed well through filtration.
In a first aspect, the present invention provides a method for synthesizing N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate, comprising the steps of:
adding concentrated sulfuric acid into a mixed solution of methanol and 2-tetrahydrofuranic acid at low temperature, and heating for esterification reaction;
after the reaction is finished, cooling the reaction liquid, adding N-methyl-1, 3-propyldiamine, and heating for reaction; after the reaction is finished, removing methanol under reduced pressure, and adding isopropanol to carry methanol to obtain N-methyl-N' -tetrahydrofuranyl propylenediamine;
adding oxalic acid or hydrate thereof into the N-methyl-N '-tetrahydrofuranyl propylenediamine solution to react to obtain the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate.
In some embodiments, the temperature of the esterification reaction is 29-65deg.C and the time of the esterification reaction is 3-36h.
In some embodiments, the N-methyl-1, 3-propyldiamine is added to the reaction solution after the reaction solution is cooled to 20-25 ℃.
Preferably, after adding N-methyl-1, 3-propyldiamine into the reaction solution, the reaction solution is heated to 40-45 ℃ and stirred for reaction for 10-15h.
In some embodiments, the temperature at which oxalic acid or oxalic acid hydrate is added is 20-30 ℃.
Preferably, the method further comprises the step of drying the prepared N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate at a drying temperature of 40-45 ℃.
In a second aspect, the invention provides application of the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate in preparing alfuzosin or isoquinoline drugs.
In a third aspect, the present invention provides a method for preparing alfuzosin or isoquinoline using N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate, wherein the method comprises the following steps:
wherein A is N or C; x is halogen; r' is H or R, R is an amino protecting group;
in the reaction process, ligand, catalyst and/or alkali are/is added into the reaction system to carry out catalytic reaction according to the situation.
In some embodiments, the ligand is selected from P (o-tolyl) 3 、PCy 3 、PPh 3 、BINAP、DPEPhos、t-BuBrettPhos、Xantphos、Dppf、Me 4 t-BuXphos、CyPFt-Bu、Dppp、JohnPhos、n-BuP(Ad) 2 、CyJohnPhos、RuPhos、P(t-Bu) 3 、SPhos、P(t-Bu) 3 ·HBF 4 One or more of t-BuXphos, xphos, brettPhos, davePhos, morDalPhos, IPr. HCl, bippyphos.
In some embodiments, the base is selected from potassium tert-butoxide, lithium bis trimethylsilylamide, DBU, sodium tert-butoxide, MTBD, potassium carbonate, potassium phosphate, or cesium carbonate.
In some embodiments, the catalyst is selected from palladium catalysts or copper catalysts.
Preferably, the palladium catalyst is PdCl 2 、Pd(OAc) 2 、[Pd(allyl)Cl] 2 、Pd(PPh 3 ) 4 、PdCl 2 [P(o-Tol) 3 ]、PdCl 2 ·(CH 3 CN) 2 、PdCl 2 (cod)、Pd(Dppf) 2 Cl 2 、Pd 2 (dba) 3 、Pd(PPh 3 ) 2 Cl 2 、Pd(acac) 2 、Pd(dba) 2 One or a mixture of more than one of themAnd (3) a compound.
The invention is further illustrated below with reference to examples.
Example 1
Preparation of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate (Compound 3)
172.0kg of methanol is added into a 500L reaction kettle, stirred, 22kg of 2-tetrahydrofuranic acid is added, 1.1kg of concentrated sulfuric acid is added into the reaction kettle at the temperature of 25-30 ℃, the temperature of the reaction liquid is raised to 30 ℃, the reaction is kept for 5 hours, the reaction liquid is cooled to 25 ℃, 16.8kg of N-methyl-1, 3-propyldiamine is added, the temperature is raised to 40-45 ℃ and stirred for 12 hours, the methanol is removed under reduced pressure at the temperature of 35-45 ℃, then 17.4kg of isopropanol is added to entrain the methanol, and the concentration is carried out under reduced pressure until no fraction is distilled out. Compound 3 was obtained. The GC diagram is shown in FIG. 1.
And adding 397.2kg of ethyl acetate into the compound 3, controlling the temperature to be 20-30 ℃, adding 24.0kg of oxalic acid dihydrate, stirring for 5 hours, centrifuging, leaching with 40.0kg of ethyl acetate, and drying the obtained material at 40-45 ℃ to obtain 49.80kg of compound 11 with a molar yield of 90.55%. GC purity: 99.43%, as shown in fig. 2.
The product of Compound 11 1 The H NMR analysis results were as follows:
1 H NMR:(400MHz,D 2 O)δ4.38-4.35(m,1H),3.95-3.92(m,1H),3.89-3.85(m,1H),3.30-3.26(m,2H),2.99(t,J＝7.6Hz,2H),2.27-2.20(m,1H),1.93-1.83(m,5H)。
obtaining the product 13 The results of the C NMR analysis were as follows:
13 C NMR:(100MHz,D 2 O)δ175.6,165.6,77.6,69.7,46.4,35.6,32.7,30.2,25.5,24.9。
LC-MS(C 19 H 19 ClN 2 O 3 )：187.1[M+H] + 。
IC report：Oxalic acid 33.68％。
content (Assay by QNMR): 65.36%.
Example 2
Preparation of isoquinoline drug from oxalate compound (Compound 11)
Preparation of compounds 6 to 12 (r=p-methoxybenzyl in this example)
Toluene (20L), compound 6 (2000 g), N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate (3200 g), sodium tert-butoxide (1100 g) and Pd were added to a reactor 2 (dba) 3 (1000g) RuPhos (1050 g), system N 2 Heating to 100 ℃ under protection for reaction for 3 hours, after the reaction is finished, cooling to 20-30 ℃, directly filtering, adding water (15L) and ethyl acetate (10L) into filtrate, collecting an organic phase, adding a citric acid solution, adjusting the pH value of the system to 3-4, separating liquid, taking an aqueous phase, extracting the organic phase with water twice (10L multiplied by 2), combining the aqueous phase, washing once with ethyl acetate (10L), adding a sodium carbonate solution and ethyl acetate (15L) into the aqueous phase, adjusting the pH value of the system to 7-8, separating liquid, collecting the organic phase, extracting the aqueous phase with ethyl acetate twice (10L multiplied by 2), combining the organic phase, performing vacuum rotary evaporation on the organic phase, purifying the organic phase with n-heptane and ethyl acetate after the rotary evaporation of the solvent, and obtaining 2150g of a product compound 12, wherein the yield is 75.9%. HPLC 96.46%, as shown in FIG. 3.
1 H NMR was resolved as follows (r=methoxybenzylamine):
1 H NMR:(400MHz,CDCl 3 )δ7.92-7.78(m,1H),7.41-7.34(m,1H),7.03(d,J＝8.8Hz,2H),6.94-6.77(m,3H),4.46-4.25(m,1H),4.18-4.07(m,2H),4.04-4.00(m,1H),4.06-4.00(m,1H),3.98(s,2H),3.93-3.89(m,4H),3.83(s,2H),3.76-3.66(m,2H),3.41-3.22(m,3H),3.02-2.87(m,3H),2.00-1.97(m,1H),1.99-1.73(m,10H)。
LC-MS(C 28 H 36 N 4 O 5 )：509.1[M+H] + ，531.1[M+Na] + 。
compound 12 to compound 13 (r=p-methoxybenzyl in this example)
The system is N 2 Under the protection, methylene dichloride (10L) and a compound 12 (1750 g) are added into a reaction kettle, trifluoroacetic acid (3500 mL) is added below 20 ℃ under the control of temperature, the reaction is carried out for 2 hours below 20 ℃, the reaction is complete, and saturated NaHCO is added into a reaction system 3 The solution was adjusted to pH 7-8, the solution was separated, the organic phase was extracted 3 times with dichloromethane (2500 mL), the organic phases were combined, evaporated in vacuo, the solvent was evaporated in vacuo and recrystallized from ethyl acetate and n-heptane to give 820g of the product compound 13 in 61.4% yield. HPLC 99.47% as shown in FIG. 4.
1 H NMR analysis was as follows:
1 H NMR:(400MHz,CDCl 3 )δ8.48(br s,1H),6.85(s,1H),6.79(s,1H),5.98(s,1H),5.38(s,2H),4.49(dd,J＝5.6,8.4Hz,1H),4.16-4.04(m,1H),4.01-3.93(m,6H),3.92-3.86(m,1H),3.58-3.50(m,1H),3.45-3.32(m,1H),3.04(tdd,J＝4.4,9.2,13.6Hz,1H),2.92(s,3H),2.34-2.18(m,2H),1.98-1.86(m,2H),1.78(tdd,J＝4.8,9.6,14.4Hz,1H)
LC-MS(C 20 H 28 N 4 O 4 )：389.1[M+H] + 。
example 3
Preparation of alfuzosin hydrochloride
Alfuzosin preparation: isoamyl alcohol (7.5L) was added to a 20L reactor, 4-amino-2-chloro-6, 7-dimethoxyquinazoline (compound 14) (1.00 kg) and N-methyl-N' -tetrahydrofuranoyl propylenediamine oxalate (1.38 kg) as well as triethylamine (1.02 kg) were added at 25 to 30℃and then the temperature was raised to 110 to 120℃and the reaction was allowed to proceed for at least 12 hours. Then cooling to 45-50 ℃, filtering, and washing the filter cake with 1L of isoamyl alcohol. Adding purified water (1.5L) and ethyl acetate (1.5L) into the filter cake, stirring for dissolution, stirring, standing and layering to obtain an ethyl acetate phase. The aqueous phase was extracted twice with ethyl acetate (1 L×2), the organic phases were combined, and evaporated in vacuo, and recrystallized from methanol after evaporation to give compound 15 (1.23 Kg), yield 75.6%: HPLC:98.74%. As shown in fig. 5.
1 H NMR analysis was as follows:
1 H NMR:(CDCl 3 )δ8.15(s,1H),7.45(s,1H),7.3(s,1H),4.69(m,1H),3.6-3.8(m,2H),3.73(s,6H),3.15(t,2H),3.0(t,2H),2.47(s,3H),2.35(s,2H),1.96-2.21(m,2H),1.8-1.9(m,2H),1.75(m,2H)。
alfuzosin hydrochloride preparation: 10L of absolute ethanol was added to the reaction vessel, followed by addition of compound 15 (1 kg) obtained above. 500g of ethanol in hydrochloric acid (30%) is added into a reaction kettle at 25-30 ℃, heated to 70-75 ℃ for dissolution, cooled to-5 ℃ and stirred at the temperature for at least 1.5 hours. The reaction solution was filtered, and the cake was washed with 1L of ethanol. The filter cake was collected, recrystallized once from ethanol and dried under vacuum at 40-45℃to give Compound 16 (990 g). The yield thereof was found to be 91.3%. HPLC 99.79%. As shown in fig. 6.
1 H NMR analysis was as follows:
1 H NMR:(CDCl 3 )δ8.20(s,1H),7.41(s,1H),7.24(s,1H),4.72(m,1H),3.71-3.89(m,2H),3.73(s,6H),3.20(m,2H),3.00(m,2H),2.47(s,3H),2.35(s,2H),1.96-2.21(m,2H),1.81-1.99(m,2H),1.75(m,2H)。
comparative example 1
Preparation of isoquinoline drugs using N-methyl-N' -tetrahydrofuranyl propylenediamine:
compound 6 to compound 12 (r=p-methoxybenzyl in this example)
Into a reaction flask were charged toluene (200 ml), compound 6 (20 g), N-methyl-N' -tetrahydrofuranyl propylenediamine (32 g), sodium t-butoxide (11 g), pd 2 (dba) 3 (10g) RuPhos (10.5 g), system N 2 Heating to 100 ℃ under protection for reaction for 3 hoursWhen the reaction is finished, the temperature is reduced to 20-30 ℃, the direct filtration is carried out, water (150 ml) and ethyl acetate (100 ml) are added into the filtrate, the organic phase is collected, the citric acid solution is added, the pH value of the system is adjusted to 3-4, the liquid is separated, the water phase is taken, the organic phase is extracted twice by water (100 ml multiplied by 2), the water phase is combined, the ethyl acetate (100 ml) is used for washing once, the sodium carbonate solution and the ethyl acetate (150 ml) are added into the water phase, the pH value of the system is adjusted to 7-8, the organic phase is collected after the liquid separation, the water phase is extracted twice by the ethyl acetate (100 ml multiplied by 2), the organic phase is combined, the solvent is distilled in a rotary way under vacuum, and then the n-heptane and the ethyl acetate are used for purification, thus 16.1g of a crude product compound 12 is obtained, and the yield is 58.2%. HPLC:70.09%, as shown in FIG. 7 a.
And (3) primary refining: methanol (60 ml) and crude product (15 g) of the compound 12 are added into a reaction bottle for heating reflux, then active carbon (0.5 g) is added for stirring reflux for 30min, the mixture is filtered while the mixture is hot, and then the hot filtrate is cooled to-5 to 0 ℃ for crystallization, thus obtaining a primary crystallization product. Repeating the above operation to obtain the secondary refined product. And drying the product in a vacuum drying oven at 40-50 ℃. 10.3g of compound 12 was weighed and purified yield: 68.7%. Total yield of this step: 58.2% 68.7% = 40.0%, HPLC:95.37%, as shown in fig. 7 b.
Preparation of compound 12 to compound 13 (r=p-methoxybenzyl in this example)
The system is N 2 Under protection, methylene chloride (45 mL) and compound 14 (8 g) were added to a reaction flask, trifluoroacetic acid (16 mL) was added at a temperature of 20℃or lower, the reaction was completed after 2 hours at a temperature of 20℃or lower, and saturated NaHCO was added to the reaction system 3 The solution was adjusted to pH 7-8, the organic phase was separated, extracted 3 times with dichloromethane (11 mL), the organic phases combined, evaporated in vacuo, the solvent evaporated in vacuo and recrystallised from ethyl acetate and n-heptane to give 3.3g of the product compound 13 in 56.7% yield. HPLC 97.19%, as shown in FIG. 8.
Comparative example 2
Preparation of alfuzosin using N-methyl-N' -tetrahydrofuranyl propylenediamine:
isoamyl alcohol (75 ml) was added to the reaction flask, 4-amino-2-chloro-6, 7-dimethoxyquinazoline (compound 14) (10 g) and N-methyl-N' -tetrahydrofuranyl propylenediamine (9.3 g) were added at 25 to 30℃and then the temperature was raised to 120 to 130℃and the reaction was continued for 20 to 24 hours. Then cooling to 45-50 ℃, filtering, and washing the filter cake with 10ml of isoamyl alcohol. The filter cake was dissolved in purified water (15 ml) and ethyl acetate (15 ml) under stirring, and the mixture was allowed to stand and separate to obtain an ethyl acetate phase. The aqueous phase was extracted twice with ethyl acetate (10 ml. Times.2), the organic phases were combined, and evaporated in vacuo, and recrystallized from methanol after evaporation to give compound 15 (10.8 g) in 66.5% yield: HPLC:93.78%. As shown in fig. 9.
Preparation of alfuzosin hydrochloride
To the reaction flask was added 100ml of ethanol, followed by addition of the compound 15 (10 g) obtained above. 5g of ethanol in hydrochloric acid (17.8%) were added to the reaction vessel at 25-30℃and stirred at this temperature for 1.5h. The reaction solution was filtered, and the cake was washed with 10ml of ethanol. The filter cake was collected, recrystallized twice from ethanol and dried under vacuum at 40-45℃to give Compound 16 (7.9 g). The yield thereof was found to be 72.2%. HPLC 98.44%. As shown in fig. 10.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (8)

  1. Application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate in preparing alfuzosin or isoquinoline drugs;
    the synthesis method of the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate comprises the following steps: adding oxalic acid or hydrate thereof into the N-methyl-N '-tetrahydrofuranyl propylenediamine solution to react to obtain the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate.
  2. 2. The use of N-methyl-N '-tetrahydrofuranyl propylenediamine oxalate according to claim 1, wherein the preparation of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate comprises the steps of:
    adding concentrated sulfuric acid into a mixed solution of methanol and 2-tetrahydrofuranic acid at low temperature, and heating for esterification reaction;
    after the reaction is finished, cooling the reaction liquid, adding N-methyl-1, 3-propyldiamine, and heating for reaction; after the reaction is finished, removing methanol under reduced pressure, and adding isopropanol to carry methanol to obtain N-methyl-N' -tetrahydrofuranyl propylenediamine;
    adding oxalic acid or hydrate thereof into the N-methyl-N '-tetrahydrofuranyl propylenediamine solution to react to obtain the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate.
  3. 3. Use of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate according to claim 2, characterized in that: the temperature of the esterification reaction is 29-65 ℃, and the time of the esterification reaction is 3-36h.
  4. 4. Use of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate according to claim 2, characterized in that: and cooling the reaction liquid to 20-25 ℃, and adding N-methyl-1, 3-propyldiamine into the reaction liquid.
  5. 5. The use of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate according to claim 4, characterized in that: after adding N-methyl-1, 3-propyl diamine into the reaction liquid, the reaction liquid is heated to 40-45 ℃ and stirred for reaction for 10-15h.
  6. 6. Use of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate according to claim 2, characterized in that: the method also comprises the step of drying the prepared N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate at 40-45 ℃.
  7. 7. The method for preparing isoquinoline drugs by adopting N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate is characterized by comprising the following steps: the compound shown in the formula II is obtained according to the following reaction formula:
    wherein A is C; x is halogen; r' is an amino protecting group;
    in the reaction process, adding a ligand, a catalyst and/or alkali into a reaction system to perform catalytic reaction;
    the ligand is selected from P (o-tolyl) 3 、PCy 3 、PPh 3 、BINAP、DPEPhos、t-BuBrettPhos、Xantphos、Dppf、Me 4 t-BuXphos、CyPFt-Bu、Dppp、JohnPhos、n-BuP(Ad) 2 、CyJohnPhos、RuPhos、P(t-Bu) 3 、SPhos、P(t-Bu) 3 ·HBF 4 、t-one or more of BuXphos, xphos, brettPhos, davePhos, morDalPhos, IPr-HCl, bippyphos;
    the base is selected from potassium tert-butoxide, lithium bistrimethylsilylamino, DBU, sodium tert-butoxide, MTBD, potassium carbonate, potassium phosphate or cesium carbonate;
    the catalyst is selected from PdCl 2 、Pd(OAc) 2 、[Pd(allyl)Cl] 2 、Pd(PPh 3 ) 4 、PdCl 2 [P(o-Tol) 3 ]、PdCl 2 ·(CH 3 CN) 2 、PdCl 2 (cod)、Pd(Dppf) 2 Cl 2 、Pd 2 (dba) 3 、Pd(PPh 3 ) 2 Cl 2 、Pd(acac) 2 、Pd(dba) 2 One or a mixture of more than one of them.
  8. 8. The method for preparing the alfuzosin medicine by adopting the N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate is characterized by comprising the following steps of: the compound shown in the formula II is obtained according to the following reaction formula:
    wherein A is N; x is halogen; r' is H;
    in the reaction process, any one or more of triethylamine, potassium tert-butoxide, lithium bistrimethylsilylamino, DBU, sodium tert-butoxide, MTBD, potassium carbonate, potassium phosphate or cesium carbonate are added into the reaction system.
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