CN114591273A - Synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate - Google Patents
Synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate Download PDFInfo
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Abstract
The invention discloses a synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate, which comprises the following steps of reacting 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; during the reaction, a ligand, a catalyst and a base are added into the reaction system according to the condition to carry out catalytic reaction.
Description
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' -tetrahydrofuran formyl propane diamine oxalate.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
N-methyl-N' -tetrahydrofuran formyl propane diamine is an important intermediate compound for preparing alfuzosin and isoquinoline medicaments, and the purity of the raw materials can directly influence the purity of the product. However, the raw material prepared by the preparation method in the prior art is generally oily, and has the following disadvantages: 1) the compound is an oily substance and is easy to wrap a solvent, so that the solvent is difficult to remove, and particularly in the process of scale-up production, the solvent residue is difficult to remove; 2) when the compound is oily matter, the material cannot be purified by adopting a conventional crystallization mode, and only can be purified by adopting a distillation mode, but the distillation purification has the problems that only impurities with large boiling point difference can be removed, and the impurities with small boiling point difference have no removal effect or have poor removal effect, so that the oily matter contains more impurities and has low purity, and the impurities can participate in subsequent reaction and generate new impurities, thereby affecting the purity of a final product.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate.
In order to achieve the purpose, the invention is realized by the following technical scheme:
in a first aspect, the invention provides a method for synthesizing N-methyl-N' -tetrahydrofuryl formyl propane diamine oxalate, which comprises the following steps:
adding concentrated sulfuric acid into a mixed solution of methanol and 2-tetrahydrofuran formic acid at a low temperature, and heating for esterification reaction;
after the reaction is finished, cooling the reaction liquid, adding N-methyl-1, 3-propyl diamine, and heating for reaction; after the reaction is finished, removing the methanol under reduced pressure, and then adding isopropanol to carry the methanol to obtain N-methyl-N' -tetrahydrofuran formyl propane diamine;
adding oxalic acid or a hydrate thereof into the N-methyl-N '-tetrahydrofuran formyl propane diamine solution for reaction to prepare the N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate.
In a second aspect, the invention provides an application of the N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate in preparation of alfuzosin or isoquinoline medicaments.
In a third aspect, the invention provides a method for preparing alfuzosin or isoquinoline drugs by using N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate, and the compound shown in the formula II is obtained by reacting according to the following reaction formula:
wherein A is N or C; x is halogen; r' is H or R, R is an amino protecting group;
during the reaction, a ligand, a catalyst and/or a base are added to the reaction system as appropriate to perform a catalytic reaction.
The beneficial effects achieved by one or more of the embodiments of the invention described above are as follows:
the oxalate is prepared from N-methyl-N' -tetrahydrofuran formyl propane diamine, the oxalate product can be precipitated to form a solid with higher purity, and when the solid salt with higher purity is used for preparing alfuzosin or isoquinoline medicaments, the obtained product has the advantages of high purity, high yield and the like.
The N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate is not easy to degrade at high temperature 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 incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are included to illustrate an exemplary embodiment of the invention and not to limit the invention.
FIG. 1 is a GC diagram of N-methyl-N' -tetrahydrofuranoyl propane diamine in example 1 of the present invention;
FIG. 2 is a GC diagram of N-methyl-N' -tetrahydrofuranoyl propane diamine oxalate prepared in example 1 of the present invention;
FIG. 3 is an HPLC chromatogram of Compound 12 prepared in example 2 of the present invention;
FIG. 4 is an HPLC chromatogram of Compound 13 prepared in example 2 of the present invention;
FIG. 5 is an HPLC chromatogram of Compound 15 prepared in comparative example 3 of the present invention;
FIG. 6 is an HPLC chromatogram of Compound 16 prepared in comparative example 3 of the present invention.
FIG. 7 is an HPLC chromatogram of Compound 12 prepared in comparative example 1 of the present invention;
FIG. 8 is an HPLC chromatogram of Compound 13 prepared in comparative example 1 of the present invention;
FIG. 9 is an HPLC chromatogram of Compound 15 prepared in comparative example 1 of the present invention;
FIG. 10 is an HPLC chromatogram of Compound 16 prepared in comparative example 1 of the present invention.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. 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 inventor uses N-methyl-N '-tetrahydrofuran formyl propane diamine to prepare alfuzosin or isoquinoline drugs, and the synthetic route of the N-methyl-N' -tetrahydrofuran formyl propane diamine is shown as follows:
however, N-methyl-N' -tetrahydrofuranoylpropanediamine (Compound 3) is an oil, and the oil has the following disadvantages: firstly, the method comprises the following steps: the compound is an oily substance which is easy to wrap the solvent, so that the solvent is difficult to remove. Especially in scale-up processes, solvent residues are more difficult to remove. The inventors tried to prepare N-methyl-N' -tetrahydrofuranoyl propane diamine using the above route, and the solvent residues in the prepared product are shown in Table 1:
TABLE 1
| Batches of | Starting materials | Product yield | Theoretical yield | Molar yield | |
| 1 | 1.58kg | 3.3kg | 2.53kg | 130％ | 30％ |
| 2 | 22.0kg | 49.8kg | 35.3kg | 141％ | 41％ |
Secondly, the method comprises the following steps: the material is oily matter, can not adopt conventional crystallization mode purification material, can only adopt the mode of distillation to purify, but the problem of distillation purification is can only get rid of the impurity that the boiling point differed greatly, to the impurity that the boiling point differed less removal effect or have not obviously to get rid of the effect, therefore contains more impurity in the oily material, and the purity can only reach about 90%.
When the oily raw material N-methyl-N' -tetrahydrofuran formyl propane diamine (compound 3) contains more solvents, the purity and the yield of the alfuzosin or isoquinoline drugs are influenced finally. In addition, the following two impurities are easy to exist in the preparation process of the N-methyl-N' -tetrahydrofuran formyl propane diamine.
The two impurities (compound 4 and compound 5) can participate in the subsequent reaction, and the generated impurities can remain in the alfuzosin or isoquinoline medicaments 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) the side reaction of the compound 5 in the isoquinoline drugs is as follows:
therefore, in order to solve the above problems, the present invention attempts to prepare N-methyl-N '-tetrahydrofuryl formylpropanediamine as an oxalate, and the salified N-methyl-N' -tetrahydrofuryl formylpropanediamine oxalate is directly precipitated from the reaction solution, and the impurities remain in the mother liquor and can be removed well by filtration.
In a first aspect, the invention provides a method for synthesizing N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate, which comprises the following steps:
adding concentrated sulfuric acid into a mixed solution of methanol and 2-tetrahydrofuran formic acid at a low temperature, and heating for esterification reaction;
after the reaction is finished, cooling the reaction liquid, adding N-methyl-1, 3-propyl diamine, and heating for reaction; after the reaction is finished, removing the methanol under reduced pressure, and then adding isopropanol to carry the methanol to obtain N-methyl-N' -tetrahydrofuran formyl propane diamine;
adding oxalic acid or a hydrate thereof into the N-methyl-N '-tetrahydrofuran formyl propane diamine solution for reaction to prepare the N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate.
In some embodiments, the temperature of the esterification reaction is 29 to 65 ℃ and the time of the esterification reaction is 3 to 36 hours.
In some embodiments, after cooling the reaction solution to 20-25 ℃, N-methyl-1, 3-propyldiamine is added to the reaction solution.
Preferably, after adding N-methyl-1, 3-propyl diamine into the reaction solution, heating the reaction solution to 40-45 ℃, and stirring for reaction for 10-15 h.
In some embodiments, the temperature at which the oxalic acid or oxalic acid hydrate is added is 20-30 ℃.
Preferably, the method also comprises a step of drying the prepared N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate, wherein the drying temperature is 40-45 ℃.
In a second aspect, the invention provides an application of the N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate in preparation of alfuzosin or isoquinoline medicaments.
In a third aspect, the invention provides a method for preparing alfuzosin or isoquinoline drugs by using N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate, and the compound shown in the formula II is obtained by reacting according to the following reaction formula:
wherein A is N or C; x is halogen; r' is H or R, R is an amino protecting group;
during the reaction, a ligand, a catalyst and/or a base are added to the reaction system as appropriate to perform a catalytic reaction.
In some embodiments, the ligand is selected from P (o-tolyl)3、PCy3、PPh3、BINAP、DPEPhos、t-BuBrettPhos、Xantphos、Dppf、Me4t-BuXphos、CyPFt-Bu、Dppp、JohnPhos、n-BuP(Ad)2、CyJohnPhos、RuPhos、P(t-Bu)3、SPhos、P(t-Bu)3·HBF4t-BuXphos, Xphos, BrettPhos, DavePhos, MordalPhos, IPr HCl, Bippyphos.
In some embodiments, the base is selected from potassium tert-butoxide, lithium bis-trimethylsilylamido, DBU, sodium tert-butoxide, MTBD, potassium carbonate, potassium phosphate, or cesium carbonate.
In some embodiments, the catalyst is selected from a palladium catalyst or a copper catalyst.
Preferably, the palladium catalyst is PdCl2、Pd(OAc)2、[Pd(allyl)Cl]2、Pd(PPh3)4、PdCl2[P(o-Tol)3]、PdCl2·(CH3CN)2、PdCl2(cod)、Pd(Dppf)2Cl2、Pd2(dba)3、Pd(PPh3)2Cl2、Pd(acac)2、Pd(dba)2One or a mixture of several of them.
The present invention will be further described with reference to the following examples.
Example 1
Preparation of N-methyl-N' -tetrahydrofuranoyl propane diamine oxalate (Compound 3)
Adding 172.0kg of methanol into a 500L reaction kettle, stirring, adding 22kg of 2-tetrahydrofuran formic acid, controlling the temperature to be 25-30 ℃, adding 1.1kg of concentrated sulfuric acid into the reaction kettle, heating the reaction liquid to 30 ℃, preserving the temperature for reaction for 5h, then cooling the reaction liquid to 25 ℃, adding 16.8kg of N-methyl-1, 3-propyl diamine, heating to 40-45 ℃, stirring for 12h, controlling the temperature to be 35-45 ℃, removing the methanol under reduced pressure, then adding 17.4kg of isopropanol with the methanol, concentrating under reduced pressure until no fraction is evaporated. Compound 3 is obtained. The GC diagram is shown in FIG. 1.
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, drying the obtained material at 40-45 ℃, and obtaining 49.80kg of the compound 11 after drying, wherein the molar yield is 90.55%. GC purity: 99.43%, as shown in FIG. 2.
Of the product of Compound 111The H NMR analysis results were as follows:
1H NMR:(400MHz,D2O)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 product13The results of C NMR analysis were as follows:
13C NMR:(100MHz,D2O)δ175.6,165.6,77.6,69.7,46.4,35.6,32.7,30.2,25.5,24.9。
LC-MS(C19H19ClN2O3)：187.1[M+H]+。
IC report：Oxalic acid 33.68％。
content (Assay by QNMR): 65.36 percent.
Example 2
Oxalate compound (compound 11) for preparing isoquinoline medicine
Toluene (20L), Compound 6(2000g), N-methyl-N' -tetrahydrofuryl propanediamine oxalate (3200g), sodium t-butoxide (1100g), Pd were charged in the reaction vessel2(dba)3(1000g) RuPhos (1050g), system in N2Heating to 100 ℃ under protection for reaction for 3 hours, after the reaction is finished, cooling to 20-30 ℃ after post-treatment, 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 a water phase, extracting the organic phase twice (10L multiplied by 2) with water, combining the water phase, washing once with ethyl acetate (10L), adding a sodium carbonate solution and ethyl acetate (15L) into the water phase, adjusting the pH value of the system to 7-8, separating liquid and collecting the organic phase, extracting the water phase with ethyl acetateTwo times (10L. times.2) were taken and the organic phases combined and rotary evaporated in vacuo and purified with n-heptane and ethyl acetate to give 2150g of product compound 12 in 75.9% yield. 96.46% by HPLC, as shown in FIG. 3.
1H NMR was resolved as follows (R ═ methoxybenzylamine):
1H NMR:(400MHz,CDCl3)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(C28H36N4O5)：509.1[M+H]+，531.1[M+Na]+。
compounds 12 to 13 (in this example R ═ p-methoxybenzyl)
System is N2Under protection, dichloromethane (10L) and compound 12(1750g) are added into a reaction kettle, trifluoroacetic acid (3500mL) is added under the temperature controlled below 20 ℃, the reaction is completed after 2 hours of reaction below 20 ℃, and saturated NaHCO is added into the reaction system3The solution was adjusted to pH 7-8, separated, the organic phase was extracted 3 times with dichloromethane (2500mL), the organic phases were combined, rotary evaporated in vacuo, the solvent evaporated and recrystallized from ethyl acetate and n-heptane to give 820g of product compound 13 with 61.4% yield. HPLC: 99.47%, as shown in FIG. 4.
1H NMR analysis was as follows:
1H NMR:(400MHz,CDCl3)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(C20H28N4O4)：389.1[M+H]+。
example 3
Preparation of alfuzosin hydrochloride
Preparation of alfuzosin: adding isoamyl alcohol (7.5L) into a 20L reaction kettle, adding 4-amino-2-chloro-6, 7-dimethoxyquinazoline (compound 14) (1.00kg) and N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate (1.38kg) and triethylamine (1.02kg) at the temperature of 25-30 ℃, then raising the temperature to 110-120 ℃, and carrying out heat preservation reaction for at least 12 hours. Then cooling to 45-50 ℃, filtering, and washing a filter cake by using 1L of isoamyl alcohol. Adding purified water (1.5L) and ethyl acetate (1.5L) into the filter cake, stirring for dissolving, stirring, standing for layering to obtain an ethyl acetate phase. The aqueous phase was extracted twice with ethyl acetate (1L × 2), the organic phases were combined, rotary evaporated in vacuo and recrystallized from methanol to give compound 15(1.23Kg) in 75.6% yield: HPLC: 98.74 percent. As shown in fig. 5.
1H NMR analysis was as follows:
1H NMR:(CDCl3)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)。
preparation of alfuzosin hydrochloride: to the reaction vessel was added 10L of anhydrous ethanol, followed by addition of the compound 15(1kg) obtained above. Adding 500g of hydrochloric acid solution (30%) of ethanol into a reaction kettle at 25-30 ℃, heating to 70-75 ℃ for dissolution, cooling to-5 ℃, and stirring at the temperature for at least 1.5 hours. The reaction solution was filtered, and the filter cake was washed with 1L of ethanol. And collecting a filter cake, recrystallizing the filter cake once by using ethanol, and drying in vacuum at 40-45 ℃ to obtain the compound 16(990 g). The yield thereof was found to be 91.3%. HPLC: 99.79%. As shown in fig. 6.
1H NMR analysis was as follows:
1H NMR:(CDCl3)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
The preparation of isoquinoline drug by using N-methyl-N' -tetrahydrofuran formyl propane diamine:
Toluene (200ml), Compound 6(20g), N-methyl-N' -tetrahydrofuranoylpropanediamine (32g), sodium t-butoxide (11g), Pd2(dba)3(10g) RuPhos (10.5g), system in N2Heating to 100 ℃ under protection for reaction for 3 hours, after the reaction is finished, cooling to 20-30 ℃ after post-treatment, directly filtering, adding water (150ml) and ethyl acetate (100ml) into filtrate, collecting an organic phase, adding a citric acid solution, adjusting the pH value of the system to 3-4, separating liquid, taking a water phase, extracting the organic phase twice (100ml multiplied by 2) by using water, combining the water phase, washing once by using ethyl acetate (100ml), adding a sodium carbonate solution and ethyl acetate (150ml) into the water phase, adjusting the pH value of the system to 7-8, separating liquid, collecting the organic phase, extracting the water phase twice (100ml multiplied by 2) by using ethyl acetate, combining the organic phase, carrying out vacuum rotary evaporation, carrying out rotary evaporation on a solvent, and purifying by using n-heptane and ethyl acetate to obtain 16.1g of a crude product compound 12, wherein the yield is 58.2%. HPLC: 70.09%, as shown in FIG. 7 a.
Primary refining: adding methanol (60ml) and a compound 12 crude product (15g) into a reaction bottle, heating and refluxing, then adding activated carbon (0.5g), stirring and refluxing for 30min, filtering while hot, and then cooling the hot filtrate to-5-0 ℃ for crystallization to obtain a primary crystallization product. Repeating the above operations to obtain secondary refined product. And (3) drying the product in a vacuum drying oven at the drying temperature of 40-50 ℃. The weight was taken to obtain 10.3g of Compound 12, purification yield: 68.7 percent. The overall yield of this step: 58.2%. 68.7%. 40.0%, HPLC: 95.37%, as shown in fig. 7 b.
Preparation of compounds 12 to 13 (R ═ p-methoxybenzyl in this example)
System is N2Under protection, dichloromethane (45mL) and compound 14(8g) are added into a reaction bottle, trifluoroacetic acid (16mL) is added under the temperature controlled below 20 ℃, the reaction is completed after 2 hours of reaction below 20 ℃, and saturated NaHCO is added into the reaction system3The solution was adjusted to pH 7-8, separated, the organic phase was extracted 3 times with dichloromethane (11mL), the organic phases were combined, rotary evaporated in vacuo, and recrystallized from ethyl acetate and n-heptane to yield 3.3g of the product compound 13, 56.7% yield. 97.19% by HPLC, as shown in FIG. 8.
Comparative example 2
The alfuzosin is prepared using N-methyl-N' -tetrahydrofuranoyl propane diamine:
adding isoamyl alcohol (75ml) into a reaction bottle, adding 4-amino-2-chloro-6, 7-dimethoxyquinazoline (compound 14) (10g) and N-methyl-N' -tetrahydrofuran formyl propanediamine (9.3g) at the temperature of 25-30 ℃, then raising the temperature to 120-130 ℃, and carrying out heat preservation reaction for 20-24 h. Then the temperature is reduced to 45-50 ℃, the filtration is carried out, and the filter cake is washed by 10ml of isoamyl alcohol. Adding purified water (15ml) and ethyl acetate (15ml) into the filter cake, stirring and dissolving, stirring, standing and demixing to obtain an ethyl acetate phase. The aqueous phase was extracted twice with ethyl acetate (10ml × 2), the organic phases were combined, rotary evaporated in vacuo and recrystallized from methanol to give compound 15(10.8g) in 66.5% yield: HPLC: 93.78 percent. As shown in fig. 9.
Preparation of alfuzosin hydrochloride
To a reaction flask was added 100ml of ethanol, followed by addition of compound 15(10g) obtained above. 5g of ethanol in hydrochloric acid (17.8%) are added to the reactor at 25-30 ℃ and stirred at this temperature for 1.5 h. The reaction solution was filtered, and the filter cake was washed with 10ml of ethanol. And collecting a filter cake, recrystallizing the filter cake twice by using ethanol, and drying in vacuum at 40-45 ℃ to obtain a 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 a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for synthesizing N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate is characterized by comprising the following steps: the method comprises the following steps:
adding concentrated sulfuric acid into a mixed solution of methanol and 2-tetrahydrofuran formic acid at a low temperature, and heating for esterification reaction;
after the reaction is finished, cooling the reaction liquid, adding N-methyl-1, 3-propyl diamine, and heating for reaction; after the reaction is finished, removing the methanol under reduced pressure, and then adding isopropanol to carry the methanol to obtain N-methyl-N' -tetrahydrofuran formyl propane diamine;
adding oxalic acid or a hydrate thereof into the N-methyl-N '-tetrahydrofuran formyl propane diamine solution for reaction to prepare the N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate.
2. The method for synthesizing N-methyl-N' -tetrahydrofuranoyl propane diamine oxalate according to claim 1, characterized in that: the temperature of the esterification reaction is 29-65 ℃, and the time of the esterification reaction is 3-36 h.
3. The method for synthesizing N-methyl-N' -tetrahydrofuryl formyl propane diamine oxalate according to claim 1, wherein: cooling the reaction liquid to 20-25 ℃, and adding N-methyl-1, 3-propyl diamine into the reaction liquid;
preferably, after adding N-methyl-1, 3-propyl diamine into the reaction solution, heating the reaction solution to 40-45 ℃, and stirring for reaction for 10-15 h.
4. The method for synthesizing N-methyl-N' -tetrahydrofuranoyl propane diamine oxalate according to claim 1, characterized in that: also comprises a step of drying the prepared N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate, wherein the drying temperature is 40-45 ℃.
The application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate in preparing alfuzosin or isoquinoline medicaments.
6. The method for preparing the alfuzosin or isoquinoline medicaments by adopting N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate is characterized by comprising the following steps of: obtaining the compound shown in the formula II according to the following reaction formula:
wherein A is N or C; x is halogen; r' is H or R, R is an amino protecting group.
7. The method of claim 6, wherein: the ligand is selected from P (o-tolyl)3、PCy3、PPh3、BINAP、DPEPhos、t-BuBrettPhos、Xantphos、Dppf、Me4t-BuXphos、CyPFt-Bu、Dppp、JohnPhos、n-BuP(Ad)2、CyJohnPhos、RuPhos、P(t-Bu)3、SPhos、P(t-Bu)3·HBF4t-BuXphos, Xphos, BrettPhos, DavePhos, MordalPhos, IPr HCl, Bippyphos.
8. The method of claim 6, wherein: the base is selected from potassium tert-butoxide, lithium bis (trimethylsilyl) amide, DBU, sodium tert-butoxide, MTBD, potassium carbonate, potassium phosphate or cesium carbonate.
9. The method of claim 6, wherein: the catalyst is selected from palladium catalysts or copper catalysts.
10. The method of claim 9The method of (2), characterized by: the palladium catalyst is PdCl2、Pd(OAc)2、[Pd(allyl)Cl]2、Pd(PPh3)4、PdCl2[P(o-Tol)3]、PdCl2·(CH3CN)2、PdCl2(cod)、Pd(Dppf)2Cl2、Pd2(dba)3、Pd(PPh3)2Cl2、Pd(acac)2、Pd(dba)2One or a mixture of several of them.
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| WO2023179068A1 (en) * | 2022-03-21 | 2023-09-28 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Drug intermediate and synthetic method, and isoquinoline derivative and synthetic method therefor |
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| US20070066824A1 (en) * | 2005-09-22 | 2007-03-22 | Anumula Raghupathi R | Preparation of alfuzosin |
| WO2007063556A2 (en) * | 2006-12-07 | 2007-06-07 | Msn Laboratories Limited | An improved and industrial process for the preparation of alfuzosin hydrochloride and its novel polymorphs |
| WO2008015525A2 (en) * | 2006-07-31 | 2008-02-07 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of alfuzosin hydrochloride |
| CN106632280A (en) * | 2016-11-24 | 2017-05-10 | 辽宁可济药业有限公司 | Method for preparing alfuzosin hydrochloride |
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| US20070066824A1 (en) * | 2005-09-22 | 2007-03-22 | Anumula Raghupathi R | Preparation of alfuzosin |
| WO2008015525A2 (en) * | 2006-07-31 | 2008-02-07 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of alfuzosin hydrochloride |
| WO2007063556A2 (en) * | 2006-12-07 | 2007-06-07 | Msn Laboratories Limited | An improved and industrial process for the preparation of alfuzosin hydrochloride and its novel polymorphs |
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| WO2023179068A1 (en) * | 2022-03-21 | 2023-09-28 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Drug intermediate and synthetic method, and isoquinoline derivative and synthetic method therefor |
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