CN107311863B

CN107311863B - Preparation method and application of chloroformate derivative

Info

Publication number: CN107311863B
Application number: CN201710609223.1A
Authority: CN
Inventors: 李世洪; 程柯; 王福雄; 左翔
Original assignee: Lier Chemical Co Ltd
Current assignee: Lier Chemical Co Ltd
Priority date: 2017-07-25
Filing date: 2017-07-25
Publication date: 2021-03-23
Anticipated expiration: 2037-07-25
Also published as: CN107311863A

Abstract

The invention discloses a preparation method and application of a chloroformate derivative, belongs to the field of chemical synthesis, and aims to provide a novel chloroformate derivative preparation method capable of meeting the industrial production requirements. In the method, the chloroformate derivative is represented by the following formula (II), and comprises the following steps: reacting a compound shown in a formula (I) with phosgene to prepare a compound shown in a formula (II); the reaction equation is as follows:

Description

Preparation method and application of chloroformate derivative

Technical Field

The invention relates to the field of chemical synthesis, in particular to a preparation method and application of a chloroformate derivative.

Background

The chloroformate derivative is used as an important pharmaceutical chemical intermediate and has important application value. At present, a new method for preparing chloroformate derivatives is urgently needed to meet the requirement of industrial application.

Disclosure of Invention

The invention aims to: aiming at the problems, the preparation method and the application of the chloroformate derivative are provided. The invention has the advantages of simple and safe production and the like, and the prepared product has higher product purity and reaction yield, and the three wastes are simple and convenient to treat, have higher application value and wide application prospect, and are worthy of large-scale popularization and application.

In order to achieve the purpose, the invention adopts the following technical scheme:

a method for preparing a chloroformate derivative represented by the following formula (II), comprising the steps of:

reacting a compound shown in a formula (I) with phosgene to prepare a compound shown in a formula (II); the reaction equation is as follows:

wherein R is C₁-C₄N is 1, 2 or 3.

Said C is₁-C₄Alkyl of (A) means C₁、C₂、C₃、C₄The alkyl group of (1) is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, etc.

Reacting the compound of formula (I) with phosgene at 0-5 ℃.

Further, R is n-propyl.

Further, n is 1.

At a temperature lower than the boiling point of phosgene, firstly, dissolving phosgene in an organic solvent, and then reacting the organic solvent with the compound of the formula (I) at a temperature of 0-5 ℃ to prepare the compound of the formula (II).

The organic solvent is selected from one or more of alkane solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents and halogenated aromatic hydrocarbon solvents.

The organic solvent is toluene.

The mass ratio of the compound shown in the formula (I) to the organic solvent is 1: 0.5 to 5.

Further, the mass ratio of the compound of formula (I) to the organic solvent is 1: 2.

and (3) after the compound of the formula (I) and phosgene react at 0-5 ℃, introducing inert gas into the mixture for polishing treatment, and obtaining the compound of the formula (II) after the polishing treatment is finished.

The inert gas is nitrogen.

When the polishing treatment is carried out, the temperature of the solution is 0-50 ℃.

Further, when the polishing treatment was carried out, the temperature of the solution was 30 ℃.

Use of the foregoing process for the preparation of a compound of the formula:

wherein R is C₁-C₄N is 1, 2 or 3.

In view of the foregoing problems, the present invention provides a method for preparing chloroformate derivatives and use thereof. The preparation method comprises the following steps of A:

reacting a compound shown in a formula (I) with phosgene at 0-5 ℃ to prepare a compound shown in a formula (II);

wherein R represents C₁-C₄N represents 1, 2 or 3.

Further, the reaction is carried out by dissolving phosgene in an organic solvent and adding the compound of formula (I) at a temperature below the boiling point of phosgene.

And (2) after the compound of the formula (I) and phosgene react at 0-5 ℃, introducing inert gas into the compound of the formula (I) for light-dispelling treatment (namely introducing the inert gas into the solution, and dispelling residual phosgene from the solution until the content of free chlorine is less than 1%), and obtaining the compound of the formula (II) after the light-dispelling treatment is finished.

Further, the present invention also provides the use of the aforementioned preparation process for the preparation of a compound of formula (III), wherein R, n is as defined above and formula (III) is as follows:

the preparation method of the chloroformate derivative has the following advantages after being verified by a plurality of experiments:

(1) the reaction operation is simple and convenient, and the flow is short;

(2) the raw materials are dropwise added, so that the reaction control is safe;

(3) the method has high product purity and reaction yield and good economic benefit;

(4) the synthesis reaction only generates acid gas, the main components of the gas are hydrogen chloride and phosgene, the gas is absorbed by liquid alkali, the neutralized gas is used as high-salinity wastewater, and the three wastes are simply and conveniently treated.

In conclusion, the invention provides a set of preparation method suitable for industrial production of chloroformate derivatives, which has the advantages of simplicity, safety and high efficiency, higher product purity and reaction yield, simple and convenient three-waste treatment, higher application value and wide application prospect.

Detailed Description

All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.

Any feature disclosed in this specification may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.

In the present invention, the meanings of English abbreviations are as follows: DMAP: 4-dimethylaminopyridine; TEBAC: benzyltriethylammonium chloride.

EXAMPLE 12 preparation of Propoxyethyl chloroformate (CEP-1#)

In this example, the analytical instrument and method were as follows:

gas chromatography normalization method:

the instrument is as follows: agilent7820A, GC with FID detector (rear well);

② chromatographic column: HP-5, 30.0 m.times.0.32 mm.times.0.25 μm;

③ temperature of sample Inlet (INJ): 280 ℃; the split ratio is as follows: 10: 1;

chromatographic column conditions: constant current mode, N₂Flow rate: 2.0 mL/min;

column temperature (COL): keeping the temperature at 60 ℃ for 2min, heating to 300 ℃ at the heating rate of 20 ℃/min, and keeping the temperature for 5 min;

detector (FID) conditions: the temperature is 300 ℃; h₂Flow rate: 40mL/min, air flow rate: 400 mL/min; tail gas blowing flow: 25 mL/min;

seventh, solvent: dichloromethane;

the system adaptability experiment: the manual sample introduction repeatability experiment RSD is less than or equal to 5 percent;

ninthly, the main peak output time is as follows: CEP-0# (2.86min), CEP-1# (4.92 min).

The low boiling impurities are characterized by the following structures:

the boiling point of (A) is 35-36 ℃;

the boiling point of (B) was 83.5 ℃.

The reaction scheme is as follows:

the inventor conducts screening of a plurality of reaction processes and post-treatment conditions, including solvent and feeding modes, reaction temperature, solvent dosage and light-dispelling temperature.

1. Solvent and feeding mode screening

(1) Mode A

Directly taking the raw material CEP-0# as a solvent, adding the CEP-0# into a reaction bottle, and directly introducing phosgene for photochemical reaction at low temperature. The method comprises the following specific steps:

experiment number CEP-01: adding 1000g of raw material CEP-0# into a reaction bottle, directly introducing phosgene at-5-0 ℃ for photochemical reaction, controlling the photochemical reaction temperature at 0-5 ℃, and reacting until the CEP-0# is controlled to be less than 1% in GC (gas chromatography).

The content of CEP-1# is 84.7% and the total amount of low-boiling impurities is 11% by gas chromatography detection.

(2) Mode B

Directly taking the raw material CEP-0# as a solvent, adding part of the CEP-0# into a reaction bottle, introducing phosgene at the temperature of-5-0 ℃ for reaction for a period of time, and continuing and dropwise adding the rest CEP-0 #. The method comprises the following specific steps:

experiment number CEP-19: firstly, 200g of CEP-0#, stirring and cooling to-5-0 ℃, and introducing phosgene. After 2h, starting to dropwise add 800g of the residual CEP-0# raw material and continuously introducing phosgene until the dropwise addition is completed, controlling the reaction temperature to be 0-5 ℃ (namely photochemical temperature) in the dropwise addition process, and preserving the temperature to be 0-5 ℃ after the dropwise addition is completed to react until the CEP-0# is controlled to be less than 1% in a GC.

The content of CEP-1# detected by gas chromatography is 93.9%, and the total amount of low-boiling point impurities is 4%.

(3) Mode C

Adding toluene as solvent into a reaction bottle, introducing phosgene at low temperature for absorption, introducing phosgene and adding CEP-0# dropwise after a period of time. The method comprises the following specific steps:

experiment number CEP-16: adding 2000g of toluene, absorbing phosgene at the temperature of-5-0 ℃, then dropwise adding 1000g of CEP-0# at the temperature of 0-5 ℃ for photochemical reaction, controlling the reaction temperature at 0-5 ℃ in the dropwise adding process, and preserving the temperature at 0-5 ℃ after the dropwise adding is finished to react until the CEP-0# controlled in the GC is less than 1%.

The content of CEP-1# is 98.5% and the total amount of low-boiling point impurities is 0.7% by gas chromatography detection.

It can be seen that in both modes A, B, the selectivity of CEP-1# is less than 95% and the total low boiling impurities content is higher; and the photochemical reaction is carried out in the mode C, so that the intermediate reaction generated by low-boiling-point impurities can be greatly reduced, the generation of the low-boiling-point impurities can be greatly reduced, the selectivity of CEP-1# can reach more than 98%, and the total amount of the low-boiling-point impurities can be controlled to be about 1%.

Therefore, the method C has better effect, i.e. the reaction has better effect under the condition of the existence of the solvent.

2. Screening of reaction temperature

The screening of photochemical reaction temperature was carried out under different temperature conditions by using CEP-0# and toluene as solvents and adding phosgene and dripping CEP-0# respectively, and the experimental data are shown in the following Table 1.

TABLE 1

Experiment number	Solvent and feeding mode	Actinic temperature	CEP-1# content	Total amount of low boilers	Reaction time
						CEP-17	Mode C	0～5℃	97.4％	1.1％	3.5h
CEP-04	Mode B	-5～0℃	90.5％	8.1％	8h
						CEP-03	Mode C	-5～0℃	96％	2.5％	4.5h
CEP-19	Mode B	0～5℃	93.9％	4％	3h
						CEP-18	Mode C	5～10℃	93.5％	4.5％	3h

The results show that the selectivity of CEP-1# is obviously influenced by photochemical temperature and time, and the reaction time is prolonged due to the fact that the photochemical temperature is too low, and the total amount of low-boiling products is obviously increased; too high a photochemical temperature, however, increases the reaction rate and likewise the total content of low-boiling products.

Therefore, the reaction temperature and time must be controlled, and the inventor confirms that the preferable photochemical temperature is 0-5 ℃ through the experimental verification of multiple batches.

3. Screening of solvent dosage

The amount of solvent used was selected and the results are shown in table 2 below.

TABLE 2

The results show that CEP-0 #: toluene ═ 1: the 2(w/w) effect is better.

By optimizing photochemical reaction conditions and comparing selectivity of CEP-1#, the currently preferred photochemical conditions are determined, namely, toluene is used as a solvent, phosgene absorption is carried out at low temperature, CEP-0# is dripped for photochemical reaction after 2 hours under the condition of keeping continuous phosgene introduction, the dripping speed is controlled, the photochemical reaction is carried out at 0-5 ℃, and after the photochemical reaction is finished, a reaction liquid is obtained.

4. Screening of reaction liquid post-treatment light-dispelling (gas purging) temperature

The reaction solutions were taken and subjected to light-driving under different temperature conditions in such a way that the temperature was slowly increased from the actinic temperature (avoiding too fast gas evolution) to the light-driving temperature, and the temperature was maintained until the light-driving was completed (free chlorine content < 1%), and the experimental results are shown in table 3 below.

TABLE 3

The results show that the light-driving temperature is too low, and the content of low-boiling products is increased more; too high a temperature for light-driving also increased the low boiling products more and the CEP-1# color became darker.

Therefore, the preferred temperature for light-expelling is 30 ℃.

5. Confirmation of optimized reaction conditions

With CEP-0 #: toluene ═ 1: taking 2(w/w) toluene as a solvent, absorbing phosgene at a low temperature (-5-0 ℃), then dropwise adding CEP-0# at a temperature of 0-5 ℃ for photochemical reaction, continuously introducing phosgene during the dropwise adding process until the photochemical reaction is finished, slowly heating to 30 ℃, using nitrogen gas for light removal at 30 ℃, and transferring the obtained product to a CEP-1# dropwise adding tank for later use after the light removal is finished.

EXAMPLE 22 preparation of propoxychloroethane (CEP)

In this example, the analytical instrument and method were as follows:

gas chromatography normalization method:

the instrument is as follows: agilent7820A, GC with FID detector (rear well);

② chromatographic column: HP-5, 30.0 m.times.0.32 mm.times.0.25 μm;

seventh, solvent: dichloromethane;

ninthly, the main peak output time is as follows: CEP-1# (4.92min), CEP (3.01 min).

The reaction scheme is as follows:

the inventor carries out the screening of feeding mode, catalyst type and dosage.

1. Feeding mode and CEP-1 #/toluene solution concentration

Using TEBAC as a catalyst, and optimizing the decarboxylation reaction at the temperature of 110-130 ℃:

(1) mode D

Paving the bottom with partial CEP-1 #/toluene solution, adding a catalyst, heating to 110 ℃, refluxing toluene, dropwise adding the rest CEP-1 #/toluene solution after decarboxylation reaction is initiated, controlling the dropwise adding speed to keep the decarboxylation reaction temperature at 110-125 ℃, and preserving heat until the decarboxylation reaction is finished after the dropwise adding is finished. The method comprises the following specific steps:

adding 50g of CEP-1 #/toluene solution and 10g of TEBAC into a 500mL four-mouth bottle, heating to 110 ℃ under a stirring state, refluxing toluene, dropwise adding the rest 250g of CEP-1 #/toluene solution after decarboxylation reaction is initiated, controlling the dropwise adding speed to maintain the decarboxylation reaction temperature at 110-125 ℃, and preserving heat and stirring until the decarboxylation reaction is completed after the dropwise adding.

(2) Mode E

And (3) paving a pure toluene solvent, adding a catalyst, heating to 110 ℃, refluxing toluene, beginning to dropwise add a CEP-1 #/toluene solution, controlling the dropwise adding speed to maintain the decarboxylation reaction temperature at 110-125 ℃, and preserving heat until the decarboxylation reaction is finished after the dropwise adding is finished. The method comprises the following specific steps:

adding 50g of toluene solution and 10g of TEABAC into a 500mL four-mouth bottle, heating to 110 ℃ under a stirring state, refluxing toluene, starting to dropwise add 300g of CEP-1 #/toluene solution, controlling the dropwise adding speed to maintain the decarboxylation reaction temperature at 110-125 ℃, preserving heat and stirring until the decarboxylation reaction is finished after the dropwise adding.

The results of the experiment are shown in table 4 below.

TABLE 4

The results show that the decarboxylation reaction carried out in the formula D has a higher yield, a higher product purity and a minimum impurity content.

2. The kind and amount of catalyst

Under the condition of the same toluene dosage, the same feeding mode and decarboxylation temperature are adopted, catalysts of different types and proportions are adopted to carry out decarboxylation reaction, and the experimental results are shown in the following table 5.

TABLE 5

The results show that DMAP is preferred as the catalyst because DMAP is less used, the yield is high and the product purity is high.

The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.

Claims

1. A method for preparing a chloroformate derivative, characterized in that the chloroformate derivative is represented by the following formula (II),

the reaction equation is as follows:

wherein R is n-propyl, and n is 1;

the method comprises the following specific steps:

at a temperature lower than the boiling point of phosgene, firstly, dissolving phosgene in an organic solvent, and then reacting the organic solvent with a compound of a formula (I) at a temperature of 0-5 ℃ to prepare a compound of a formula (II); the organic solvent is toluene.

2. The method of preparing a chloroformate derivative according to claim 1, wherein the mass ratio of the compound of formula (I) to the organic solvent is 1: 2.

3. the method for preparing a chloroformate derivative according to any one of claims 1 to 2, wherein after the reaction between the compound of formula (I) and phosgene is completed at 0 to 5 ℃, an inert gas is introduced into the compound of formula (I) to perform a quenching treatment, and after the quenching treatment is completed, the compound of formula (II) is obtained.

4. The method of producing a chloroformate derivative according to claim 3, wherein the temperature of the solution at the time of the light-expelling treatment is 30 ℃.

5. The method of preparing a chloroformate derivative according to claim 3, wherein said inert gas is nitrogen.

6. Use of a process according to any one of claims 1-2, 4, 5 for the preparation of a compound of the formula:

wherein R is n-propyl and n is 1.

7. Use of the process of claim 3 for the preparation of a compound of the formula:

wherein R is n-propyl and n is 1.