阅读说明：本技术 用于制备卡沙兰的方法 (Process for the preparation of casalas ) 是由 林幸邦 周吉 于 2020-05-18 设计创作，主要内容包括：本发明公开了一种通过使水杨酰胺与碳酸二乙酯在碱金属乙醇盐的存在下反应来制备卡沙兰的方法。(The invention discloses a process for the preparation of casalak by reacting salicylamide with diethyl carbonate in the presence of an alkali metal ethoxide.)

1. A process for preparing compounds of the formula (3) by two subsequent reactions REAC1 and REAC2

In the first reaction REAC1, salicylamide is reacted with diethyl carbonate in the presence of an alkali metal ethoxide to provide a compound of formula (3-X)

In the second reaction REAC2, reacting the compound of formula (3-X) obtained from REAC1 with a bronsted acid to provide a compound of formula (3);

x is Na or K;

the alkali metal ethoxide is NaOEt or KOEt.

2. The method of claim 1, wherein

For REAC1, diethyl carbonate and salicylamide were first mixed and the alkali metal ethoxide was then added to the mixture.

3. The method of claim 1 or 2, wherein

The molar amount of alkali metal ethoxide in REAC1 is 1 to 2 times the molar amount of salicylamide.

4. Method according to one or more of claims 1 to 3, wherein

The molar amount of diethyl carbonate in REAC1 is 1 to 5 times the molar amount of salicylamide.

5. Method according to one or more of claims 1 to 4, wherein

The alkali metal ethoxide is NaOEt, and X is Na.

6. Method according to one or more of claims 1 to 5, wherein

The molar amount of bronsted acid in REAC2 is 1 to 2 times the molar amount of alkali metal ethoxide.

7. Method according to one or more of claims 1 to 6, wherein

The pKa of the Bronsted acid is lower than that of the compound of formula (3-X).

8. Method according to one or more of claims 1 to 7, wherein

The Bronsted acid is selected from HCl, H₂SO₄、HNO₃、HClO₄HBr and H₃PO₄A group of combinations thereof.

9. Method according to one or more of claims 1 to 8, wherein

The Bronsted acid is preferably used in the form of an aqueous solution.

10. Method according to one or more of claims 1 to 9, wherein

For REAC2, the Bronsted acid is added to the compound of formula (3-X).

11. Method according to one or more of claims 1 to 10, wherein

Between REAC1 and REAC2, the reaction mixture obtained from REAC1 was mixed with water.

12. The method of claim 11, wherein

The amount of water is 0.1 to 1.5 times the combined weight of salicylamide, diethyl carbonate and alkali metal ethoxide.

13. The method of claim 11 or 12, wherein

Water was added to the reaction mixture obtained from REAC 1.

14. Method according to one or more of claims 1 to 13, wherein

After REAC2, the reaction mixture is cooled in cooling COOL3 to a temperature TEMP3 of-20 to 10 ℃ before isolating the compound of formula (3) from the reaction mixture obtained from REAC 2.

15. Method according to one or more of claims 1 to 14, wherein

The compound of formula (3-X) is not isolated between REAC1 and REAC 2.

16. The method of claim 14 or 15, wherein

The compound of formula (3) is not isolated between REAC2 and COOL 3.

Background

The casalak is an analgesic.

WO 00/46182a1 discloses in example 1 the preparation of carbazochrome from salicylamide with ethyl chloroformate in a pyridine and acetonitrile solvent in 85% yield.

Ethyl chloroformate is a highly toxic chemical whose use is regulated (e.g. in china) and therefore poses risks to the environment, in particular to workers during production. Furthermore, it is sensitive to moisture and reacts with water, and when it is handled, corresponding measures need to be taken.

The use of both pyridine and acetonitrile adds cost to the process because these solvents must be discarded in some way or they must be recovered, both of which again contribute to cost.

There is a need for a process for the preparation of casalak in high yield and purity, but with less disadvantages than the process disclosed in WO 00/46182a 1.

It has been unexpectedly found that the use of diethyl carbonate provides high yields, high purity, without the need for the solvent pyridine or acetonitrile; furthermore, diethyl carbonate is non-toxic, its use is not as regulated as ethyl chloroformate, and diethyl carbonate is not moisture sensitive, it does not react with water, all of which makes its handling easier and safer to the environment.

Abbreviations

A compound of the formula (3) of carbazochrome

Salicylamide compounds of formula (1)

Disclosure of Invention

The subject of the invention is a process for preparing compounds of formula (3) by two subsequent reactions REAC1 and REAC2

In a first reaction REAC1, salicylamide is reacted with diethyl carbonate in the presence of an alkali metal ethoxide to provide a compound of formula (3-X)

Reacting the compound of formula (3-X) obtained from REAC1 with a bronsted acid in a second reaction REAC2 to provide a compound of formula (3);

x is Na or K;

the alkali metal ethoxide is NaOEt or KOEt.

Detailed Description

The three substances salicylamide, diethyl carbonate and alkali metal ethoxide may be mixed in any order for REAC 1; preferably, for REAC1, diethyl carbonate and salicylamide are first mixed and then the alkali metal ethoxide is added to the mixture.

Preferably, the molar amount of alkali metal ethoxide in REAC1 is 1 to 2 times, more preferably 1 to 1.75 times, even more preferably 1 to 1.5 times, in particular 1.1 to 1.5 times, more in particular 1.2 to 1.4 times the molar amount of salicylamide.

Preferably, the alkali metal ethoxide is in ethanol solution; more preferably, the ethanolate is used in the form of its ethanolate at a concentration of 10 to 25% by weight, even more preferably 15 to 25% by weight, in particular 18 to 22% by weight, more particularly 19 to 22% by weight, based on the weight of the solution.

Preferably, the molar amount of diethyl carbonate in REAC1 is 1 to 5 times, more preferably 1 to 4 times, even more preferably 2 to 4 times, in particular 2.5 to 3.5 times the molar amount of salicylamide.

Preferably, REAC1 is carried out at a reaction temperature TEMP1 of 20 to 160 deg.C, more preferably 40 to 140 deg.C, even more preferably 60 to 120 deg.C, in particular 60 to 100 deg.C, more in particular 70 to 90 deg.C, even more in particular 75 to 85 deg.C.

Preferably, the reaction TIME of REAC1 TIME1 is 30 minutes to 8 hours, more preferably 1 to 6 hours, even more preferably 1 to 4 hours, in particular 1 to 3 hours, more in particular 1.5 to 2.5 hours.

REAC1 can be carried out at ambient or elevated pressure, preferably adjusted in such a way that the desired reaction temperature can be set according to the vapor pressure of the reaction mixture.

Preferably, the alkali metal ethoxide is NaOEt and X is Na.

Preferably, the molar amount of bronsted acid in REAC2 is 1 to 2 times, more preferably 1.01 to 1.8 times, even more preferably 1.05 to 1.6 times, in particular 1.05 to 1.4 times, more in particular 1.1 to 1.2 times the molar amount of alkali metal ethoxide.

The Bronsted acid protonates the compound of formula (3-X) and thus the pKa of the Bronsted acid is lower than that of the compound of formula (3-X).

Preferably, the Bronsted acid is selected from the group consisting of HCl, H₂SO₄、HNO₃、HClO₄HBr and H₃PO₄A group of compounds; more preferably the Broensted acid is selected from the group consisting of HCl, H₂SO₄And H₃PO₄A group of compounds; even more preferably the bronsted acid is HCl.

The Bronsted acid is preferably used in the form of an aqueous solution.

In case the Bronsted acid is HCl, the HCl is preferably used in the form of an aqueous solution having a concentration of 3-12.6M, more preferably 5-12.6M, even more preferably 7-12.6M, especially 9-12.6M, more especially 11-12.6M, even more especially 11.5-12.6M. In one embodiment, the HCl is concentrated HCl. In another embodiment, HCl is used in the form of an aqueous solution with a concentration of 12M.

Another way to characterize HCl that may be used in the form of an aqueous solution is a weight percent HCl concentration, such as 10 to about 38 weight percent, 16 to about 38 weight percent, 22 to about 38 weight percent, 28 to 38 weight percent, 33 to 38 weight percent, based on the total weight of the aqueous HCl solution.

The skilled person knows the concentration of aqueous HCl available on the market; even the highest commercially available concentration can be used for REAC 2.

For REAC2, the compound of formula (3-X) and the Bronsted acid may be mixed in any manner, preferably the Bronsted acid is added to the compound of formula (3-X), more preferably the Bronsted acid is added to the reaction mixture from REAC1 containing the compound of formula (3-X).

Preferably, REAC2 is carried out at a reaction temperature TEMP2 of 20-100 deg.C, more preferably 30-100 deg.C, even more preferably 30-90 deg.C, in particular 30-80 deg.C, more in particular 30-70 deg.C, even more in particular 30-60 deg.C, in particular 40-60 deg.C, more in particular 45-55 deg.C.

Preferably, the reaction TIME of REAC2 TIME2 is 0.5 to 4 hours, more preferably 0.5 to 2 hours, even more preferably 0.5 to 1.5 hours.

REAC2 can be carried out at ambient or elevated pressure, preferably adjusted in such a way that the desired reaction temperature can be set according to the vapor pressure of the reaction mixture.

Between REAC1 and REAC2, the reaction mixture obtained from REAC1 may be mixed with water; the amount of water may be from 0.1 to 1.5 times, preferably from 0.3 to 1.2 times, more preferably from 0.3 to 0.9 times, even more preferably from 0.4 to 0.8 times, especially from 0.5 to 0.7 times the combined weight of salicylamide, diethyl carbonate and alkali metal ethoxide.

Preferably, the addition of water is carried out under TEMP 2.

Preferably, water is added to the reaction mixture obtained from REAC 1.

Preferably, after REAC2, the reaction mixture is cooled in cooling COOL3 to a temperature TEMP3 of-20 to 10 ℃, more preferably-10 to 5 ℃, even more preferably-5 to 5 ℃, in particular 0 ℃.

COOL3 is carried out before isolating the compound of formula (3) from the reaction mixture obtained from REAC 2.

The compound of formula (3) can be isolated after REAC2 or after COOL3 by standard methods known to the person skilled in the art, such as filtration and subsequent drying. The filter cake obtained by filtration may be washed with ethanol, water or both; and any drying may be performed under vacuum and/or at elevated temperature (e.g. under vacuum and at a temperature of 40-60 ℃).

In one embodiment, the method includes

·REAC1，

REAC2, and

·COOL3

preferably, the method comprises

·REAC1，

Mixing the reaction mixture obtained from REAC1 with water

REAC2, and

·COOL3。

preferably, the compound of formula (3-X) is not separated between REAC1 and the mixing of the reaction mixture obtained from REAC1 with water.

Preferably, the compound of formula (3-X) is not isolated between the mixing of the reaction mixture obtained from REAC1 with water and REAC 2.

Preferably, the compound of formula (3-X) is not isolated between REAC1 and REAC 2.

Preferably, the compound of formula (3) is not isolated between REAC2 and COOL 3.

Preferably, the compound of formula (3-X) is not isolated between REAC1 and COOL3 and the compound of formula (3) is not isolated.

Preferably, the mixing of REAC1, REAC2, the reaction mixture obtained from REAC1 with water and the COOL3 are carried out in one and the same reaction vessel without transferring any reaction mixture from this reaction vessel to any other reaction vessel and without any intermediate separation of the compound of formula (3-X), and the separation of the compound of formula (3) is carried out only after REAC2 or only after COOL3 if COOL3 is carried out.

Preferably, the reaction mixture after REAC1 is a suspension of alkali metal salts of casamantane.

Preferably, the reaction mixture obtained from REAC1 after mixing it with water is a solution of the alkali metal salt of carbazol.

Preferably, the reaction mixture after REAC2 is a suspension of casalak.

Preferably, the reaction mixture after COOL3 is a suspension of casalak.

Examples of the invention

Abbreviations

eq, molar equivalents, if not otherwise stated

Material

Diethyl carbonate Acros (Thermo Fisher Scientific) 99%

Salicylamide Michelin Inc. (Macklin Inc.), Shanghai, China, 99%

Analytical method

HPLC method for determining the purity of casamantane

Parameters of the instrument

Blank space: acetonitrile/water (1/1, v/v)

Sample solution

Stability: the solution is stable at 4 ℃ for 2 days

Example 1

A1.5L reactor was charged with 253g of diethyl carbonate (2.15mol, 3.0 equiv.) and 100g of salicylamide (0.715mol, 1.0 equiv.). The mixture was a suspension and stirred for 15 minutes. 309g of 20% by weight EtONa/EtOH (0.93mol, 1.3 eq.) were then charged to the reactor. The reaction mixture became a clear solution. The reaction mixture was heated to 80 ℃ and stirred at 80 ℃ for 2 hours. A white precipitate was observed. The reaction mixture was cooled to 50 ℃. 387g of water were added and the reaction mixture was stirred for about 15 minutes until it became a clear solution. 109g of 12M HCl (1.07mol, 1.5 eq.) are then added dropwise to the reactor over a period of 1 hour, a precipitate forming when 12M HCl is added. The reaction mixture was cooled to 0 ℃ over 2 hours. The suspension was filtered to give a filter cake. 231g of ethanol was added to the reactor and stirred for 15 minutes, and the filter cake was washed with ethanol from the reactor. The filter cake is then washed with 515g of water and 231g of ethanol and dried at 50 ℃ under vacuum (10kPa) for 5 hours. 107g of casalane were obtained as white crystalline product.

The yield is 90 percent

HPLC purity > 99.9%.

¹H NMR(400MHz,DMSO)δ7.95(dd,J＝8.0,1.4Hz,1H),7.80(td,J＝8.1,1.7Hz,1H),7.46-7.36(m,2H)。