阅读说明：本技术 一种odmt,n-fmoc-氨基丁基-1,3-丙二醇的合成方法 (Synthesis method of ODMT, N-FMOC-aminobutyl-1, 3-propanediol ) 是由 蒋红亮 王力刚 于 2021-08-31 设计创作，主要内容包括：本发明属于医药中间体技术领域,具体涉及一种ODMT,N-FMOC-氨基丁基-1,3-丙二醇的合成方法。本发明通过以丙二酸二乙酯、4-溴丁腈作为起始原料,依次通过取代反应,还原反应,FMOC保护,DMT保护,进而合成了ODMT,N-FMOC-氨基丁基-1,3-丙二醇,该合成路线合成产品的纯度高、收率高,易于操作,为ODMT,N-FMOC-氨基丁基-1,3-丙二醇的合成提供了一个优良的路线。(The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of ODMT, N-FMOC-aminobutyl-1, 3-propylene glycol. According to the invention, diethyl malonate and 4-bromobutyronitrile are used as initial raw materials, and are subjected to substitution reaction, reduction reaction, FMOC protection and DMT protection in sequence, so that ODMT, N-FMOC-aminobutyl-1, 3-propanediol is synthesized.)

1. A synthetic method of ODMT, N-FMOC-aminobutyl-1, 3-propanediol is characterized in that the preparation method comprises the following steps:

(1) putting sodium ethoxide and absolute ethyl alcohol into a reactor, adding diethyl malonate and 4-bromobutyronitrile, and stirring for reaction at 20-30 ℃ to obtain a compound A

；

(2) Dissolving the compound A in tetrahydrofuran, using nitrogen for protection, adding lithium aluminum hydride at the temperature of 3-7 ℃, reacting, heating to 13-15 ℃, and carrying out heat preservation reaction to obtain a compound B

；

(3) Putting the compound B, water and sodium carbonate into a reactor, uniformly stirring, controlling the temperature to be 0-10 ℃, dissolving the fluorenylmethoxycarbonyl acyl chloride into tetrahydrofuran, adding the mixture into the reactor, and stirring for reaction to obtain a compound C

；

(4) Dissolving the compound C in dichloromethane, adding triethylamine, stirring, cooling to 0-5 ℃, dissolving 4,4' -dimethoxy triphenylchloromethane in dichloromethane, adding, preserving heat for reaction, heating to 15-20 ℃, and reacting to obtain ODMT, N-FMOC-aminobutyl-1, 3-propanediol。

2. The method for synthesizing ODMT, N-FMOC-aminobutyl-1, 3-propanediol according to claim 1, wherein the mass ratio of sodium ethoxide, diethyl malonate and 4-bromobutyronitrile in the step (1) is 9: 3-5: 3.

3. The method for synthesizing ODMT, N-FMOC-aminobutyl-1, 3-propanediol according to claim 1, wherein the mass ratio of the compound A to the lithium aluminum hydride in the step (2) is 10: 5-7.

4. The method for synthesizing ODMT, N-FMOC-aminobutyl-1, 3-propanediol according to claim 1, wherein the mass ratio of the compound B, sodium carbonate and fluorenylmethoxycarbonyl chloride in the step (3) is 10:3: 11-13.

5. The method for synthesizing ODMT, N-FMOC-aminobutyl-1, 3-propanediol according to claim 1, wherein the mass ratio of the compound C, triethylamine and 4,4' -dimethoxytriphenylchloromethane in the step (4) is 10: 3-5: 6-9.

Technical Field

The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of ODMT, N-FMOC-aminobutyl-1, 3-propylene glycol.

Background

ODMT, N-FMOC-aminobutyl-1, 3-propanediol (also known as 6-fluorenylmethoxycarbonylamino-2- ((di (4-methoxyphenyl) (phenyl) methoxy) methyl) hexan-1-ol) is an important derivative of di (4-methoxyphenyl) methanol, can be widely applied to the field of medical intermediates, meanwhile, in some components for microbial detection, virus detection or germ detection, ODMT, N-FMOC-aminobutyl-1, 3-propylene glycol is also an important intermediate for synthesizing detection components, however, no synthetic route of ODMT, N-FMOC-aminobutyl-1, 3-propanediol has been reported in the prior art, and there is a need to provide a synthetic route with high synthetic efficiency and high purity.

Disclosure of Invention

The technical problems to be solved by the invention are as follows: aiming at the problems, the ODMT, N-FMOC-aminobutyl-1, 3-propanediol synthesis method is provided.

In order to solve the technical problems, the invention adopts the following technical scheme:

a synthetic method of ODMT, N-FMOC-aminobutyl-1, 3-propanediol comprises the following steps:

(1) putting sodium ethoxide and absolute ethyl alcohol into a reactor, adding diethyl malonate and 4-bromobutyronitrile, and stirring at 20-30 ℃ for reaction to obtain a compound A, wherein the structural formula of the compound A is as follows

；

(2) Dissolving the compound A in tetrahydrofuran, using nitrogen for protection, adding lithium aluminum hydride at the temperature of 3-7 ℃, reacting, heating to 13-15 ℃, and carrying out heat preservation reaction to obtain a compound B, wherein the structural formula of the compound B is as follows

；

(3) Putting the compound B, water and sodium carbonate into a reactor, uniformly stirring, controlling the temperature to be 0-10 ℃, dissolving the fluorenylmethoxycarbonyl acyl chloride into tetrahydrofuran, adding the mixture into the reactor, and stirring for reaction to obtain a compound C, wherein the structural formula of the compound C is as follows

；

(4) Dissolving the compound C in dichloromethane, adding triethylamine, stirring for reaction, cooling to 0-5 ℃, dissolving 4,4' -dimethoxy triphenylchloromethane in dichloromethane, adding, preserving heat for reaction, heating to 15-20 ℃, and reacting to obtain ODMT, N-FMOC-aminobutyl-1, 3-propanediol with the structural formula shown in the specification

。

Preferably, the mass ratio of the sodium ethoxide, the diethyl malonate and the 4-bromobutyronitrile in the step (1) is 9: 3-5: 3. Preferably, the mass ratio of the compound A to the lithium aluminum hydride in the step (2) is 10: 5-7.

Preferably, the mass ratio of the compound B, the sodium carbonate and the fluorenylmethoxycarbonyl chloride in the step (3) is 10:3: 11-13.

Preferably, the mass ratio of the compound C, triethylamine and 4,4' -dimethoxytriphenylchloromethane in the step (4) is 10: 3-5: 6-9.

Compared with other methods, the method has the beneficial technical effects that:

according to the invention, diethyl malonate and 4-bromobutyronitrile are used as initial raw materials, and are subjected to substitution reaction, reduction reaction, FMOC protection and DMT protection in sequence, so that ODMT, N-FMOC-aminobutyl-1, 3-propanediol is synthesized.

Drawings

FIG. 1 is a nuclear magnetic spectrum of ODMT, N-FMOC-aminobutyl-1, 3-propanediol, a product prepared by method 8 in example 4.

Detailed Description

A synthetic method of ODMT, N-FMOC-aminobutyl-1, 3-propanediol comprises the following steps:

(1) taking materials according to the mass ratio of 9: 3-5: 3 of sodium ethoxide, diethyl malonate and 4-bromobutyronitrile, putting sodium ethoxide and absolute ethyl alcohol into a reactor, adding diethyl malonate and 4-bromobutyronitrile, and stirring at 20-30 ℃ for reaction to obtain a compound A;

(2) taking materials according to the mass ratio of the compound A to the lithium aluminum hydride of 10: 5-7, dissolving the compound A in tetrahydrofuran, adding the lithium aluminum hydride at the temperature of 3-7 ℃ under the protection of nitrogen, reacting, heating to 13-15 ℃, and preserving heat for reaction to obtain a compound B;

(3) taking materials according to the mass ratio of the compound B to the sodium carbonate to the fluorenylmethoxycarbonyl chloride of 10:3: 11-13, putting the compound B, water and the sodium carbonate into a reactor, uniformly stirring, controlling the temperature to be 0-10 ℃, dissolving the fluorenylmethoxycarbonyl chloride in tetrahydrofuran, adding the tetrahydrofuran into the reactor, and stirring for reaction to obtain a compound C;

(4) taking materials according to the mass ratio of the compound C to triethylamine to the 4,4 '-dimethoxy triphenylchloromethane of 10: 3-5: 6-9, dissolving the compound C in dichloromethane, adding triethylamine, stirring for reaction, cooling to 0-5 ℃, dissolving the 4,4' -dimethoxy triphenylchloromethane in dichloromethane, adding, preserving heat for reaction, heating to 15-20 ℃, and reacting to obtain ODMT, N-FMOC-aminobutyl-1, 3-propanediol.

Example 1

Synthesis of Compound A:

the method 1 comprises the steps of adding 900 g of sodium ethoxide into a reaction bottle, then adding 1000 g of absolute ethyl alcohol, dropwise adding 300 g of diethyl malonate, adding 300 g of 4-bromobutyronitrile, controlling the temperature to be 20 ℃, reacting for 8 hours at 300r/min, adding 800 mL of water, stirring, dissolving, then adding 1L of ethyl acetate for extraction, separating liquid, extracting a water phase with 500mL of ethyl acetate, combining, washing with 500mL of brine, and concentrating under reduced pressure to obtain the compound A, wherein the molar yield is 89.3%, and the purity is 98.2%.

The method 2 comprises the following steps: adding 900 g of sodium ethoxide into a reaction bottle, then adding 1000 g of absolute ethanol, dropwise adding 300 g of diethyl malonate, adding 300 g of 4-bromobutyronitrile, controlling the temperature to be 20 ℃, reacting for 8 hours at 300r/min, adding 800 mL of water, stirring, dissolving, then adding 1L of ethyl acetate for extraction, separating liquid, extracting a water phase with 500mL of ethyl acetate, combining, washing with 500mL of brine, and concentrating under reduced pressure to obtain the compound A, wherein the molar yield is 91.2%, and the purity is 98.6%.

Example 2

Compound A was prepared according to method 1 of the examples.

Preparation of compound B:

the method 3 comprises the following steps: placing 100g of the compound A and 1400mL of tetrahydrofuran into a reaction bottle, stirring for dissolving, adding 50g of lithium aluminum hydride at 3 ℃ under the protection of nitrogen, carrying out heat preservation reaction for 3h, adding 15% liquid alkali by mass fraction, carrying out heat preservation stirring for 1h, standing for 30min, pouring out supernatant, adding 500mL of tetrahydrofuran into the reaction bottle, pulping once, combining tetrahydrofuran phases, and concentrating under reduced pressure to obtain a compound B, wherein the molar yield is 88.1% and the purity is 97.7%.

The method 4 comprises the following steps: placing 100g of the compound A and 1400mL of tetrahydrofuran into a reaction bottle, stirring for dissolving, adding 70g of lithium aluminum hydride at 3 ℃ under the protection of nitrogen, carrying out heat preservation reaction for 3h, adding 15% liquid alkali by mass fraction, carrying out heat preservation stirring for 1h, standing for 30min, pouring out supernatant, adding 500mL of tetrahydrofuran into the reaction bottle, pulping once, combining tetrahydrofuran phases, and concentrating under reduced pressure to obtain a compound B, wherein the molar yield is 86.3% and the purity is 97.5%.

Example 3

Compound B was prepared using method 1 of example 2.

The method 5 comprises the following steps: placing 100g of compound B, 600mL of water and 30g of sodium carbonate into a reaction bottle, stirring and mixing, controlling the temperature to be 0 ℃, dissolving 110g of fluorenylmethoxycarbonyl chloride in 150mL of tetrahydrofuran, adding the tetrahydrofuran into the reaction bottle, keeping the temperature for reaction for 4 hours, separating tetrahydrofuran, adding 300mL of water, stirring, adding 500mL of ethyl acetate for extraction once, separating liquid, extracting once with 200mL of ethyl acetate, combining extracted organic phases, washing once with saline, drying, concentrating and passing through a column to obtain the compound B, wherein the molar yield is 82.3%, and the purity is 96.2%.

The method 6 comprises the following steps: placing 100g of compound B, 600mL of water and 30g of sodium carbonate into a reaction bottle, stirring and mixing, controlling the temperature to be 0 ℃, dissolving 130g of fluorenylmethoxycarbonyl chloride in 150mL of tetrahydrofuran, adding the tetrahydrofuran into the reaction bottle, keeping the temperature for reaction for 4 hours, separating tetrahydrofuran, adding 300mL of water, stirring, adding 500mL of ethyl acetate for extraction once, separating liquid, extracting once with 200mL of ethyl acetate, combining extracted organic phases, washing once with saline, drying, concentrating and passing through a column to obtain the compound B, wherein the molar yield is 85.6%, and the purity is 98.1%.

Example 4

Compound C was prepared according to method 6 of example 3.

The method 7 comprises the following steps: dissolving 100g of the compound C in 1L of dichloromethane, adding 50g of triethylamine, stirring for 30min at 300r/min, cooling to 0 ℃, dissolving 90g of 4,4' -dimethoxy triphenylchloromethane in 200mL of dichloromethane, adding the dichloromethane into a reaction system, heating to 15 ℃, preserving heat for reaction for 1.5h, adding 30m of methanol for quenching reaction, stirring for 0.5h, adding 200mL of brine for washing, separating, drying with anhydrous sodium sulfate, concentrating to the residual 400mL, adding 250g of silica gel for sample mixing, draining and passing through a column to obtain ODMT, N-FMOC-aminobutyl-1, 3-propanediol, wherein the molar yield is 81.3%, and the purity is 98.2%.

The method 8 comprises the following steps: dissolving 100g of the compound C in 1L of dichloromethane, adding 30g of triethylamine, stirring for 30min at the speed of 300r/min, cooling to 0 ℃, dissolving 60g of 4,4' -dimethoxy triphenylchloromethane in 200mL of dichloromethane, adding the dichloromethane into a reaction system, heating to 15 ℃, preserving heat for reaction for 1.5h, adding 30m of methanol for quenching reaction, stirring for 0.5h, adding 200mL of brine for washing, separating, drying with anhydrous sodium sulfate, concentrating to the residual 400mL, adding 250g of silica gel for sample mixing, draining and passing through a column to obtain ODMT, N-FMOC-aminobutyl-1, 3-propanediol, wherein the molar yield is 84.3%, and the purity is 98.5%.