Racemization preparation method of apremilast and intermediate thereof

Abstract

The invention belongs to the technical field of medicines and chemistry, and discloses a racemization preparation method of a compound shown in a formula II. According to the method, in an organic solvent, a compound shown in a formula III reacts with sulfide and an initiator to obtain a raceme II compound, and the reaction formula of the raceme II compound is shown as follows: # imgabs0 #. Compared with the prior art, the raceme of the formula II is prepared through a one-step method, the reaction is free of high temperature, and the yield is high; the method is free of pressurization, simple in route, low in cost and stable in process, ee of the product is smaller than or equal to 5.0%, preferably smaller than or equal to 2.0%, the yield reaches 95% or above, the recovery reaction can be continuously and repeatedly carried out, and the method has very high application value in industry.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and chemistry, and relates to a racemization preparation method of apremilast and its intermediates. Background Art

[0002] Apremilast has a CAS number of 608141-41-9, a chemical name of (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, and a chemical structure as shown in the following formula I:

[0003]

[0004] Apremilast is a first-in-class oral selective phosphodiesterase-4 inhibitor developed by Gelgene Corporation. It has been approved by the FDA and EMA regulatory agencies for the treatment of active psoriasis (PSA) and moderate to severe plaque psoriasis. It works by regulating the intracellular pro-inflammatory and anti-inflammatory factor action network and inhibits the activity of multiple inflammatory markers involved in the pathogenesis of psoriasis. This drug is the first oral drug approved for the treatment of psoriasis in the past 20 years and the first oral drug approved for psoriatic arthritis in the past 15 years.

[0005] (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine-N-acetyl-L-leucine salt obtained after the splitting of 3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]-benzylamine is an important intermediate for the synthesis of Apremilast. The R-configuration compound after splitting loses its use value. Chinese patent application number CN201910991024.0 discloses a method for recovering 3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]-benzylamine, and the reaction formula is as follows:

[0006]

[0007] Compound I undergoes two-step reactions, elimination and addition, to obtain the racemic compound II. The addition reaction requires the use of a pressure autoclave, which is pressurized to 0.3-0.8 MPa and reacts for 40 hours to generate the target product. The reaction has high energy consumption, complicated operations, a long time, and high costs, which is not conducive to large-scale industrial production. Summary of the invention

[0008] The invention aims to overcome the problems of long reaction steps, high energy consumption, long time, high cost, waste of resources and the like in the prior art, and provides a method for recovering 3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]-benzylamine. The method is simple to prepare, and the obtained 3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]-benzylamine can continue to participate in the reaction process, so as to achieve recycling and greatly reduce the cost of Apremilast raw material medicine.

[0009] The first aspect of the present invention provides a racemization preparation method of a compound of formula II, and the reaction formula is as follows:

[0010]

[0011] The compound of formula III is reacted in the presence of sulfide, initiator and organic solvent to obtain the racemic compound of formula II.

[0012] The racemic compound of formula II has an ee≤5.0%, preferably an ee≤2.0%.

[0013] The sulfide is selected from methyl thioglycolate, methyl mercaptopropionate, methyl mercaptobutyrate, ethyl mercaptoacetate, benzyl mercaptan, phenylethyl mercaptan, furfuryl mercaptan, dodecanethiol, 1,6-hexanedithiol, bis-mercaptoethyl thioether alcohol, pentaerythritol tetrakis-3-mercaptopropionate, trimethylolpropane tris(3-mercaptopropionate) alcohol, preferably dodecanethiol, 1,6-hexanedithiol, bis-mercaptoethyl thioether alcohol, pentaerythritol tetrakis-3-mercaptopropionate, trimethylolpropane tris(3-mercaptopropionate) alcohol, and more preferably pentaerythritol tetrakis-3-mercaptopropionate.

[0014] The initiator is selected from azobisisobutyronitrile (AIBN), azobisisovaleronitrile, azobisisoheptanenitrile, azobisisobutyramidine hydrochloride, dimethyl azobisisobutyrate, azobisisobutylimidazole hydrochloride, azoisobutylcyanamide, dibenzoyl peroxide, dodecyl peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, m-chloroperbenzoic acid, potassium persulfate, preferably AIBN and azobisisovaleronitrile, more preferably AIBN.

[0015] The molar ratio of the reaction initiator, the sulfide and the compound of formula III is 0.01-0.05:0.1-0.5:1, preferably 0.02:0.1:1.

[0016] The organic solvent is selected from one or more of aromatic hydrocarbons, ethers, nitriles, halogenated alkanes or alkanes, the aromatic hydrocarbons are selected from toluene, o-xylene, m-xylene or p-xylene, the ethers are selected from tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, the nitriles are selected from acetonitrile, the halogenated hydrocarbons are selected from chloroform, the alkanes are selected from n-heptane or n-octane, preferably toluene, o-xylene, m-xylene, p-xylene, and more preferably toluene.

[0017] The reaction temperature is 20-80°C, preferably 60-80°C.

[0018] The reaction time is 4 to 36 hours, preferably 18 to 24 hours, for example 19 hours, 20 hours, 21 hours, 22 hours, 23 hours.

[0019] The second aspect of the present invention provides a method for preparing Apremilast, which comprises splitting the compound of formula II with a splitting agent to obtain a compound of formula IV, and further performing a dehydration cyclization reaction to obtain Apremilast. For example, Apremilast is prepared by referring to the method in the prior art CN101683334A, and the route is as follows:

[0020]

[0021] The method provided by the present invention has the following significant advantages:

[0022] 1) The present invention provides a racemization preparation method of an apremilast intermediate compound, which solves the waste of resources caused in the existing synthesis process and is more in line with the concept of green chemistry;

[0023] 2) The one-step method of the present invention is used to prepare the racemic form of formula II, and the reaction is free of high temperature and pressure, and the route is simple, the cost is low, the process is stable, the product ee is ≤5.0%, preferably ≤2.0%, the yield is above 95%, and the recovery reaction can be continuously repeated, which has high application value in industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The drawings described herein are used to provide further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0025] Figure 1 This is the HPLC spectrum of compound III before racemization in Example 1.1;

[0026] Figure 2 This is the HPLC spectrum of Compound II after racemization in Example 1.1. DETAILED DESCRIPTION

[0027] The present invention will be further described below in conjunction with specific examples. It should be understood that the following detailed description of the technical solution of the present invention with examples will help to further understand the advantages and effects of the technical solution of the present invention, and the examples do not limit the protection scope of the present invention, which is determined by the claims.

[0028] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0029] Example 1.1 Preparation of Compound II

[0030]

[0031] Compound III (R)-1-(3-ethoxy-4-methoxyphenyl)-(methylsulfonyl)ethylamine (50 g, 0.183 mol, ee>98.0%, as Figure 1 As shown), toluene 250mL, pentaerythritol tetra-3-mercaptopropionate (8.94g, 0.0183mol), azobisisobutyronitrile (0.6g, 3.66mmol) were stirred under magnetic stirring, and the temperature was slowly raised to 60°C under nitrogen protection. The reaction progress was tracked by HPLC. The reaction was complete after 20h. 250mL of water was added to the reaction solution, and the pH value was adjusted to 4-5 with 2N dilute hydrochloric acid. The liquid was separated and the organic phase was discarded. The aqueous phase was adjusted to pH 9-10 with 2N sodium hydroxide solution, and extracted twice with ethyl acetate (2×200mL). The organic phases were combined, washed once with saturated brine (100mL), dried over anhydrous sodium sulfate (20g), filtered, and the filtrate was concentrated to dryness under reduced pressure at 35-40°C to obtain a white solid (Compound II, yield 95.5%; ee=0.47%, as Figure 2 MS (ESI): m / z = 274.35 [M + H] +

[0032] Examples 1.2 to 1.11 Referring to the operation method of Example 1.1, the type of organic solvent was changed to prepare the product compound II, as shown in Table 1 below:

[0033] Table 1

[0034]

[0035]

[0036] The results in Table 1 show that when the solvent is selected from aromatic hydrocarbons, such as toluene, o-xylene, m-xylene, and p-xylene, the recovery rate of the racemic compound of Formula II is high.

[0037] Examples 1.12 to 1.17 refer to the operation method of Example 1.1, and change the reaction time to prepare the product compound II, as shown in Table 2 below:

[0038] Table 2

[0039]

[0040] Combining the results in Table 1 and Table 2, it is shown that when the reaction time is 20 h, ee ≤ 2.0%. Further extension of the time does not change the ee value and yield much. From the perspective of energy saving and environmental protection, a reaction time of 20 h was selected for subsequent experiments.

[0041] Examples 1.18-1.22 Referring to the operation method of Example 1.1, the reaction temperature was changed to prepare the product compound II, as shown in Table 3 below:

[0042] Table 3

[0043]

[0044] The results in Table 1 and Table 3 show that when the reaction temperature is 60-80°C, the ee value requirement can be met, and the recovery rate of the racemic compound of Formula II is high. From the perspective of energy saving, the preferred reaction time is 60°C.

[0045] Examples 1.23-1.34 Referring to the operation method of Example 1.1, the initiator was changed to prepare the product compound II, as shown in Table 4 below:

[0046] Table 4

[0047]

[0048]

[0049] The results in Table 1 and Table 4 show that when the initiator is AIBN or azobisisovaleronitrile, the recovery rate of the racemic compound of Formula II is high and the ee value meets the requirements.

[0050] Examples 1.35-1.44 Referring to the operation method of Example 1.1, the sulfide was changed to prepare the product compound II, as shown in Table 5 below:

[0051] Table 5

[0052]

[0053] The results in Table 5 show that the ee values ​​of Examples 1.42 to 1.44 are ≤ 2%, which all meet the requirements.

Claims

1. A racemization preparation method of a compound of formula II, characterized in that: The steps include: The compound of formula III is racemized under the conditions of an initiator, a sulfide and an organic solvent to obtain a compound of formula II, and the reaction formula is shown below:

2. The preparation method according to claim 1, characterized in that: The racemic compound of formula II has an ee≤5.0%, preferably an ee≤2.0%.

3. The preparation method according to claim 1, characterized in that: The sulfide is selected from methyl thioglycolate, methyl mercaptopropionate, methyl mercaptobutyrate, ethyl mercaptoacetate, benzyl mercaptan, phenylethyl mercaptan, furfuryl mercaptan, dodecanethiol, 1,6-hexanedithiol, bis-mercaptoethyl thioether alcohol, pentaerythritol tetrakis-3-mercaptopropionate, trimethylolpropane tris(3-mercaptopropionate) alcohol, preferably dodecanethiol, 1,6-hexanedithiol, bis-mercaptoethyl thioether alcohol, pentaerythritol tetrakis-3-mercaptopropionate, trimethylolpropane tris(3-mercaptopropionate) alcohol, and more preferably pentaerythritol tetrakis-3-mercaptopropionate.

4. The preparation method according to claim 1, characterized in that: The initiator is selected from azobisisobutyronitrile, azobisisovaleronitrile, azobisisoheptylonitrile, azobisisobutyramidine hydrochloride, dimethyl azobisisobutyrate, azobisisobutylimidazoline hydrochloride, azoisobutylcyanamide, dibenzoyl peroxide, dodecyl peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, m-chloroperbenzoic acid, and potassium persulfate.

5. The preparation method according to claim 4, characterized in that: The initiator is selected from azobisisobutyronitrile or azobisisovaleronitrile.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the reaction initiator, the sulfide and the compound III is 0.01-0.05:0.1-0.5:

1.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the reaction initiator, the sulfide and the compound III is 0.02:0.1:

1.

8. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of aromatic hydrocarbons, ethers, nitriles, halogenated alkanes or alkanes, the aromatic hydrocarbons are selected from toluene, o-xylene, m-xylene or p-xylene, the ethers are selected from tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, the nitriles are selected from acetonitrile, the halogenated alkanes are selected from chloroform, the alkanes are selected from n-heptane or n-octane, preferably toluene, o-xylene, m-xylene, p-xylene, and more preferably toluene.

9. The preparation method according to claim 1, characterized in that: The reaction temperature is 20-80°C, preferably 60-80°C; The reaction time is 4 to 36 hours, preferably 18 to 24 hours.

10. A method for preparing Apremilast, characterized in that: A racemization preparation method of a compound of formula II according to any one of claims 1 to 9, and a separation and dehydration cyclization method to prepare Apremilast, wherein the reaction formula is as follows:

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