CN109651187B

CN109651187B - Synthesis method of (S) -N' - (2-benzyloxypropylene) formylhydrazine

Info

Publication number: CN109651187B
Application number: CN201811619850.4A
Authority: CN
Inventors: 邵宁; 王春春
Original assignee: Ningbo Xinji New Material Technology Co ltd
Current assignee: Dongying Ruigang Investment Service Co ltd
Priority date: 2018-12-28
Filing date: 2018-12-28
Publication date: 2021-07-09
Anticipated expiration: 2038-12-28
Also published as: CN109651187A

Abstract

A method for synthesizing (S) -N' - (2-benzyloxypropylene) formylhydrazine comprises the following steps: firstly, reacting (S) -2-benzyloxy propionic acid with an acylating reagent to obtain (S) -2-benzyloxy propionyl chloride; then adding a palladium barium sulfate catalyst into o-xylene, and then carrying out reduction reaction for 15-30 minutes in a hydrogen atmosphere; then adding (S) -2-benzyloxy propionyl chloride, and continuously heating and refluxing in a hydrogen atmosphere to react until the reaction mixture does not absorb hydrogen; after the reaction is finished, filtering the catalyst, and removing o-xylene to obtain (S) -2-benzyloxy propionaldehyde; reacting (S) -2-benzyloxy propionaldehyde with formylhydrazine, removing the solvent after the reaction is finished, and then carrying out post-treatment to obtain the final product (S) -N' - (2-benzyloxy propylene) formylhydrazine. According to the invention, the acylation reagent which is low in price and safer and more environment-friendly in reaction and the palladium barium sulfate catalyst which can be recycled for multiple times are used as reaction raw materials, so that the reaction process is more in line with the atom economy principle, and the reaction is milder.

Description

Synthesis method of (S) -N' - (2-benzyloxypropylene) formylhydrazine

Technical Field

The invention relates to the technical field of posaconazole intermediate synthesis, and particularly designs a synthesis method of (S) -N' - (2-benzyloxypropylidene) formylhydrazine.

Background

Posaconazole (chemical name: 4- [4- [4- [ [ (3R,5R) -5- (2, 4-difluorophenyl) -5- (1,2, 4-triazol-1-ylmethyl) oxolan-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S,3S) -2-hydroxypentan-3-yl ] -1,2, 4-triazol-3-one, english name: Posaconazole) having the following structural formula:

developed by Mr. Probaba company in America, approved by FDA in US in 2006 and 9 months, and is a high-lipophilicity broad-spectrum triazole antifungal agent. The product is Noxafil (Nocofei), and is an oral suspension for preventing invasive Aspergillus and Candida infections in thirteen or more years old, and treating oropharyngeal Candida infections and fluconazole and voriconazole-resistant oropharyngeal Candida infections.

(S) -N' - (2-benzyloxypropylene) formylhydrazine is an intermediate for the synthesis of posaconazole and has the following structural formula:

PCT International patent application WO 2013042138 discloses the synthesis of (S) -N' - (2-benzyloxypropylene) carbohydrazide from (S) -2-benzyloxypropionic acid, as shown in the following formula:

the method has the advantages of long preparation steps, more side reactions and low yield, and particularly, diisobutylaluminum hydride which is expensive and easy to catch fire during aftertreatment is used in the preparation process, and anhydrous conditions are very harsh under the reaction conditions, so that the production risk of (S) -N' - (2-benzyloxypropylidene) formylhydrazine is high, and the cost is high.

Chinese patent application No. 201711471531.9 discloses a method for synthesizing (S) -N' - (2-benzyloxypropylene) carbohydrazide as shown below, which avoids the use of diisobutylaluminum hydride but has poor atom economy in the whole reaction route, wherein the use of ethylenediamine and the post-treatment cause a certain environmental pressure:

(ii) a Therefore, a new method for synthesizing (S) -N '- (2-benzyloxypropylene) formylhydrazine is needed to meet the requirement of an important intermediate (S) -N' - (2-benzyloxypropylene) formylhydrazine required for the synthesis of posaconazole.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a method for preparing a high-purity aluminum alloy by using diisobutylaluminum hydride which is easy to catch fire when in aftertreatment as a reaction raw material and does not adopt ethylenediamine which causes certain environmental pressure; but adopts an acylation reagent with low price and safer and more environment-friendly reaction and a palladium barium sulfate catalyst which can be recycled for multiple times as reaction raw materials, the reaction process better conforms to the atom economy principle, and the reaction is milder.

In order to solve the technical problems, the invention adopts the technical scheme that: a method for synthesizing (S) -N' - (2-benzyloxypropylene) formylhydrazine comprises the following specific synthetic routes:

the synthesis method of the (S) -2-benzyloxy propionaldehyde comprises the following specific steps:

(1) firstly, (S) -2-benzyloxy propionic acid (CAS login number: 100836-85-9) reacts with an acylation reagent to obtain (S) -2-benzyloxy propionyl chloride;

(2) then adding a palladium barium sulfate catalyst (Rosenmon catalyst) into o-xylene, and then carrying out reduction reaction for 15-30 minutes in a hydrogen atmosphere; then adding the (S) -2-benzyloxy propionyl chloride prepared by the method in the step (1), and continuously heating and refluxing in a hydrogen atmosphere to react until the reaction mixture does not absorb hydrogen; after the reaction is finished, filtering the catalyst, and removing o-xylene to obtain (S) -2-benzyloxy propionaldehyde;

(3) and (S) -2-benzyloxy propionaldehyde prepared in the step (2) is reacted with formylhydrazine, the solvent is removed after the reaction is finished, and then the final product (S) -N' - (2-benzyloxy propylene) formylhydrazine is obtained after post-treatment.

The molar ratio of the (S) -2-benzyloxypropionic acid to the acylating agent in step (1) of the present invention is 1:1.0 to 1.5, preferably 1:1 to 1.2; by adopting the raw material collocation of the proportioning structure, the yield and the reaction completion degree of the intermediate product can be improved, and the generation of byproducts is reduced.

The acylating agent in step (1) of the present invention may be one of thionyl chloride, oxalyl chloride and phosphorus trichloride.

In the step (1), toluene is used as a solvent, wherein the reaction time is 4-8 hours, and the reaction temperature adopts reflux temperature (the boiling point of toluene) for reaction.

In the step (2), the hydrogen atmosphere is kept at a pressure of 0.05-0.15MPa in the reaction system.

The step (2) of the invention is heated and refluxed to react until the reaction mixture does not absorb hydrogen, namely, the pressure of the hydrogen in the reaction system is not changed.

The palladium barium sulfate catalyst in the step (2) of the invention has a mass percent of palladium in the catalyst of 8-12%.

The molar ratio of palladium to (S) -2-benzyloxypropionyl chloride in the palladium barium sulfate catalyst in step (2) of the present invention is 1:8 to 12, and more preferably 1:9 to 10.

In step (3) of the present invention, the molar ratio of (S) -2-benzyloxypropanal to formylhydrazine is 1:0.8 to 1.5, and more preferably 1:1 to 1.2.

The post-treatment in the step (3) of the invention comprises the following steps: adding ethyl acetate into the reactant after the solvent is removed, stirring for 0.5-2 hours at 25-30 ℃, filtering, removing the ethyl acetate from the obtained filtrate, adding petroleum ether, stirring for 0.5-2 hours at 25-30 ℃, filtering out the precipitate, and drying the precipitate to obtain the product (S) -N' - (2-benzyloxypropylene) formylhydrazine.

The invention has the advantages and beneficial effects that:

1. the method comprises the steps of firstly, taking palladium barium sulfate as a catalyst, taking (S) -2-benzyloxy propionic acid and an acylation reagent as raw materials, preparing (S) -2-benzyloxy propionaldehyde in two steps, and then reacting with formylhydrazine to prepare a target product; the palladium barium sulfate catalyst adopted by the invention can be recycled, and the utilization efficiency is equivalent to the effect of directly adopting the catalyst, so that the synthesis cost can be effectively reduced; and diisobutyl aluminum hydride which is expensive and easy to catch fire during post-treatment is not adopted in the preparation process, so that the operation safety is fully improved, the production cost is reduced, the preparation process is mild, the operation is easy, and the industrial production is easy to realize.

2. The method has high atom economy and simple post-treatment, and can obtain (S) -2-benzyloxy propionaldehyde only by filtering and removing the solvent; then reacting with formylhydrazine, washing and filtering to obtain a target product; without recrystallization, column chromatography and other steps which are difficult to operate industrially, and the like, has the advantages of high yield, easy operation and easy industrial production.

3. The invention provides a brand-new method for preparing (S) -N '- (2-benzyloxypropylene) formylhydrazine, which provides a good solution for obtaining the product and can ensure that an intermediate (S) -N' - (2-benzyloxypropylene) formylhydrazine for synthesizing posaconazole is obtained by a more ideal method; the method also obtains the (S) -N '- (2-benzyloxy propylene) formylhydrazine by an acylation reagent, a palladium barium sulfate catalyst and a formylhydrazine reaction mode and way for the first time, and provides a more economic and environment-friendly method for obtaining the (S) -N' - (2-benzyloxy propylene) formylhydrazine which is an intermediate of the posaconazole.

Detailed Description

The present invention will be described in further detail below by way of examples, but the present invention is not limited to only the following examples.

Example 1

1. A250 ml round bottom flask was charged with (S) -2-benzyloxypropionic acid (18.02 g, 0.10mol), thionyl chloride (14.16 g, 0.12mol) and 150ml of toluene, heated under reflux, and the tail gas was taken up in sodium hydroxide solution. After 6 hours of reaction, heating was stopped, and toluene and excess thionyl chloride were removed by rotary evaporation to give 18.87 g (0.095mol) of (S) -2-benzyloxypropionyl chloride in 95% yield.

2. Adding 10.00 g (reduced to 0.01mol of metallic palladium) of palladium barium sulfate catalyst with 10 percent of palladium content into 100ml of o-xylene, refluxing for 20 minutes under hydrogen atmosphere (0.1MPa pressure), and then cooling to room temperature; then, 19.86 g (0.10mol) of the (S) -2-benzyloxypropionyl chloride prepared in step (1) was added, and then, hydrogenation was continued under a hydrogen atmosphere of 0.1MPa and refluxed until the reaction mixture did not absorb hydrogen (the hydrogen pressure in the reaction system did not decrease). After the reaction is finished, the mixture is cooled to room temperature, the catalyst is removed by filtration, and the product (S) -2-benzyloxy propionaldehyde is obtained by 14.76 g and the yield is 90 percent after the solvent o-xylene is removed by rotary evaporation;

3. dissolving 9.01 g (0.15mol) of formylhydrazine in 130ml of methanol, cooling to 0 ℃, adding 130ml of toluene solution in which 24.63 g (0.15mol) of (S) -2-benzyloxy propionaldehyde is dissolved, slowly heating to 25-30 ℃, and continuing to stir at the temperature for reaction for 3 hours; after the reaction is finished, the solvent is removed by rotary evaporation, 60ml of ethyl acetate is added into the residue, the mixture is stirred for 1.5 hours at the temperature of 25-30 ℃, the precipitate is filtered out, 60ml of petroleum ether is added into a semisolid product obtained after the ethyl acetate is removed from the mother liquor, the precipitate is filtered out after the mixture is stirred for 1.5 hours at the temperature of 25-30 ℃, and the product (S) -N' - (2-benzyloxypropylidene) formylhydrazine is obtained after drying, 26.28(0.128ml) g and the yield is 85 percent.

And (3) comparison: the step (2) is repeated, the catalyst is changed into the palladium barium sulfate catalyst recovered in the step (2), and 14.76 g of the product (S) -2-benzyloxy propionaldehyde is obtained, and the yield is 90%. The activity of the catalyst is not reduced, and the catalyst can be repeatedly utilized, so that the production cost is reduced.

(S) -2-Benzyloxypropionaldehyde MS (M/z):164 (M)⁺)135,107,91,77。

Infrared analysis of (S) -2-benzyloxypropanal: at 1454cm^-1Has a vibration peak of benzene ring skeleton at 698cm^-1、 738cm^-1Bending vibration peaks outside a benzene ring-CH surface exist at two positions; at 1094cm^-1The stretching peak of C-O-C is present at 1733 cm^-1Has a stretching vibration peak of carbonyl at 1374cm^-1The frequency doubling peak of C-H stretching vibration and the base frequency Fermi resonance generated by the C-H stretching vibration of the carbonyl exist; at 2870cm^-1Is represented by-CH₃The stretching vibration peak of (1).

Example 2

1. A250 ml round bottom flask was charged with (S) -2-benzyloxypropionic acid (18.02 g, 0.10mol), oxalyl chloride (12.70 g, 0.10mol) and 150ml toluene, heated under reflux, and the tail gas was taken up in sodium hydroxide solution. After 8 hours of reaction, heating was stopped, and toluene and excess oxalyl chloride were removed by rotary evaporation to give 18.27 g (0.092mol) of (S) -2-benzyloxypropionyl chloride in 92% yield.

2. 10.00 g of palladium barium sulfate catalyst (reduced to 0.01mol of metallic palladium) with 10 percent of palladium content is added into 100ml of toluene, the mixture is refluxed for 20 minutes under the hydrogen atmosphere (0.1MPa) and then cooled to room temperature, 19.86 g (0.10mol) of (S) -2-benzyloxy propionyl chloride is added, and then hydrogenation is continued under the hydrogen atmosphere of 0.1MPa and the mixture is refluxed until the reaction mixture does not absorb hydrogen (the hydrogen pressure in the reaction system is not reduced). After the reaction is finished, the mixture is cooled to room temperature, the catalyst is removed by filtration, and the solvent toluene is removed by rotary evaporation to obtain 14.76 g of the product (S) -2-benzyloxy propionaldehyde with the yield of 90%;

3. dissolving 9.61 g (0.16mol) of formylhydrazine in 150ml of methanol, cooling to 0 ℃, adding 150ml of toluene solution dissolved with 28.90 g (0.176mol) of (S) -2-benzyloxy propionaldehyde, slowly heating to 25-30 ℃, and continuing to stir at the temperature for reaction for 3 hours; after the reaction is finished, the solvent is removed by rotary evaporation, 70ml of ethyl acetate is added into the residue, the mixture is stirred for 2 hours at 25-30 ℃, the precipitate is filtered out, 70ml of petroleum ether is added into the semisolid product obtained after the ethyl acetate is removed from the mother liquor, the precipitate is filtered out after the mixture is stirred for 2 hours at 25-30 ℃, and the product (S) -N' - (2-benzyloxypropylidene) formylhydrazine 30.47(0.148mol) g is obtained after drying, and the yield is 84%.

And (3) comparison: the step 2 is repeated, the catalyst is changed into the palladium barium sulfate catalyst recovered in the step 2, and 14.76 g of the product (S) -2-benzyloxy propionaldehyde is obtained, and the yield is 90%. Indicating that the catalyst activity did not decrease.

Example 3

1. A250 ml round bottom flask was charged with (S) -2-benzyloxypropionic acid (18.02 g, 0.10mol), phosphorus trichloride (15.07 g, 0.11mol) and 150ml of toluene, heated under reflux, and the tail gas was taken up in sodium hydroxide solution. After 7 hours of reaction, heating was stopped, and toluene and excess thionyl chloride were removed by rotary evaporation to give 19.06 g (0.096mol) of (S) -2-benzyloxypropionyl chloride in 96% yield.

2. 12 g of palladium barium sulfate catalyst with 10 percent of palladium content (calculated as 0.012mol of metal palladium) is added into 100ml of toluene, the mixture is refluxed for 20 minutes under the hydrogen atmosphere (0.1MPa) and then cooled to room temperature, 21.41 g (0.108mol) of (S) -2-benzyloxy propionyl chloride is added, and then hydrogenation is continued under the hydrogen atmosphere of 0.1MPa and the mixture is refluxed until the reaction mixture does not absorb hydrogen (the hydrogen pressure in the reaction system does not decrease). After the reaction is finished, cooling the mixture to room temperature, filtering to remove the catalyst, and removing the solvent toluene by rotary evaporation to obtain 16.13(0.098mol) g of the product (S) -2-benzyloxy propionaldehyde with the yield of 91%;

3. dissolving 9.61 g (0.15mol) of formylhydrazine in 150ml of methanol, cooling to 0 ℃, adding 150ml of toluene solution dissolved with 29.56 g (0.18mol) of (S) -2-benzyloxy propionaldehyde, slowly heating to 25-30 ℃, and continuing to stir at the temperature for reaction for 3 hours; after the reaction is finished, the solvent is removed by rotary evaporation, 80ml of ethyl acetate is added into the residue, the mixture is stirred for 2 hours at 25-30 ℃, the precipitate is filtered out, 80ml of petroleum ether is added into a semisolid product obtained after the ethyl acetate of the mother liquor is removed, the precipitate is filtered out after the stirring for 2 hours at 25-30 ℃, and the product (S) -N' - (2-benzyloxypropylidene) formylhydrazine is 31.90 g (0.155mol) and the yield is 86 percent after drying.

And (3) comparison: the step 2 is repeated, the catalyst is changed into the palladium barium sulfate catalyst recovered in the step 2, and the product (S) -2-benzyloxy propionaldehyde is 16.13 g, and the yield is 91%. Indicating that the catalyst activity did not decrease.

The yield of the invention is a round-off yield which is a conventional calculation mode in the industry.

The embodiments show that the method of the invention has high atom economy, simple and safe post-reaction treatment, easy operation and easy industrial production.

Claims

1. A method for synthesizing (S) -N' - (2-benzyloxy propylene) formylhydrazine is characterized by comprising the following steps: the specific synthetic route of the method is as follows:

2. the method for synthesizing (S) -N' - (2-benzyloxypropylene) carbohydrazide according to claim 1, wherein: the synthesis method comprises the following specific steps:

(1) firstly, reacting (S) -2-benzyloxy propionic acid with an acylating reagent to obtain (S) -2-benzyloxy propionyl chloride;

(2) then adding a palladium/barium sulfate catalyst into o-xylene, and then carrying out reduction reaction for 15-30 minutes in a hydrogen atmosphere; then adding the (S) -2-benzyloxy propionyl chloride prepared by the method in the step (1), and continuously heating and refluxing in a hydrogen atmosphere to react until the reaction mixture does not absorb hydrogen; after the reaction is finished, filtering the catalyst, and removing o-xylene to obtain (S) -2-benzyloxy propionaldehyde;

3. The method for synthesizing (S) -N' - (2-benzyloxypropylidene) carbohydrazide according to claim 2, wherein: the molar ratio of the (S) -2-benzyloxy propionic acid to the acylating agent in the step (1) is 1: 1.0-1.5; the acylating reagent in the step (1) is one of thionyl chloride, oxalyl chloride and phosphorus trichloride.

4. The method for synthesizing (S) -N' - (2-benzyloxypropylene) carbohydrazide according to claim 3, wherein: the molar ratio of the (S) -2-benzyloxy propionic acid to the acylating agent in the step (1) is 1: 1-1.2.

5. The method for synthesizing (S) -N' - (2-benzyloxypropylidene) carbohydrazide according to claim 2, wherein: in the step (1), toluene is used as a solvent, wherein the reaction time is 4-8 hours, and the reaction temperature adopts reflux temperature for reaction.

6. The method for synthesizing (S) -N' - (2-benzyloxypropylidene) carbohydrazide according to claim 2, wherein: in the step (2), the hydrogen atmosphere is to keep the pressure in the reaction system at 0.05-0.15 MPa; and (2) heating, refluxing and reacting until the reaction mixture does not absorb hydrogen, namely the pressure of the hydrogen in the reaction system is unchanged.

7. The method for synthesizing (S) -N' - (2-benzyloxypropylidene) carbohydrazide according to claim 2, wherein: the palladium/barium sulfate catalyst in the step (2), wherein the mass percent of palladium in the catalyst is 8-12%; the molar ratio of palladium to (S) -2-benzyloxypropionyl chloride in the palladium/barium sulfate catalyst in step (2) is 1: 8-12.

8. The method for synthesizing (S) -N' - (2-benzyloxypropylidene) carbohydrazide according to claim 2, wherein: the molar ratio of palladium to (S) -2-benzyloxypropionyl chloride in the palladium/barium sulfate catalyst in step (2) is 1: 9-10.

9. The method for synthesizing (S) -N' - (2-benzyloxypropylidene) carbohydrazide according to claim 2, wherein: in the step (3), the molar ratio of the (S) -2-benzyloxy propionaldehyde to the formylhydrazine is 1: 0.8-1.5.

10. The method for synthesizing (S) -N' - (2-benzyloxypropylidene) carbohydrazide according to claim 9, wherein: the post-treatment in the step (3) is as follows: adding ethyl acetate into the reactant after the solvent is removed, stirring for 0.5-2 hours at 25-30 ℃, filtering, removing the ethyl acetate from the obtained filtrate, adding petroleum ether, stirring for 0.5-2 hours at 25-30 ℃, filtering out the precipitate, and drying the precipitate to obtain the product (S) -N' - (2-benzyloxypropylene) formylhydrazine.