WO2016066116A1

WO2016066116A1 - Preparation method of apremilast and intermediate thereof

Info

Publication number: WO2016066116A1
Application number: PCT/CN2015/093149
Authority: WO
Inventors: 王小龙; 李鑫源; 李志亚; 刘彦龙; 张喜全
Original assignee: 南京安源生物医药科技有限公司; 连云港润众制药有限公司
Priority date: 2014-10-29
Filing date: 2015-10-29
Publication date: 2016-05-06
Also published as: CN105622380A; CN105622380B

Abstract

Provided are a preparation method of Apremilast and intermediates thereof. Also provided is an Apremilast intermediate shown by Formula III, wherein Apremilast is obtained with the compound of Formula III sequentially reacting with methyl sulfinate, reductively-aminated, salified with asymmetric acids, and reacting with 3-acetyl amino phthalic anhydride. The method for preparing Apremilast provided in the present application can avoid using an n-butyl lithium n-hexane solution, which reduces the production cost, facilitates the operating process, improves security in the industrial production, and is more suitable for industrialized continuous production. The yield of the method for preparing 3-acetyl amino phthalic anhydride provided in the present application is increased to 81% which has higher yield and is extremely suitable for industrialized production of Apremilast.

Description

Apost's preparation method and its intermediates

Cross-reference to related applications

The present application claims priority to Chinese Patent Application No. 20141059195, filed on Jan. 29, 2014, to the

Technical field

The present application relates to the field of pharmaceutical and chemical industry, and in particular to a method for synthesizing Apster.

Background technique

Apremilast is a PDE4 inhibitor developed by Celgene and its chemical name is 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4 -Acetylaminoisoindoline-1,3-dione having a structure as shown in Formula A. Apster was approved by the US FDA on March 25, 2014. It has clinically developed multiple indications for rheumatoid arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and the first approved by the FDA. The indication is adult psoriatic arthritis (PsA). Different from the commonly used anti-TNF monoclonal antibody in clinical practice, Apster is an oral anti-rheumatic drug with a new mechanism of action, which has great market potential.

US 2013/0217919 Al discloses a method for synthesizing a Pust, which requires a solution of n-butyllithium n-hexane, which is inconvenient to operate and has a greater risk; in addition, 3-acetylaminophthalic anhydride The yield is lower.

Summary of invention

In one aspect, the application provides a compound of Formula III,

Wherein L is a halogen, preferably Cl, Br or I, more preferably Cl or Br.

Another aspect of the present application provides a process for the preparation of a compound of formula III, comprising the steps of reacting a compound of formula II with a halogenating reagent to provide a compound of formula III,

Wherein L is a halogen, preferably Cl, Br or I, more preferably Cl or Br.

In some embodiments, the halogenating agent is selected from the group consisting of dichlorohydantoin, liquid bromine, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), or phenyl trimethyl Ammonium tribromide, preferably dichlorohydantoin or phenyltrimethylammonium tribromide. In some embodiments, the molar ratio of the compound of Formula II to the halogenating agent is from 1:0.5 to 1:2, preferably from 1:0.75 to 1:1.

In some embodiments, the compound of formula II is prepared by reacting a compound of formula I with an ethylating agent,

In some embodiments, the compound of formula I and the ethylating agent are preferably reacted in the presence of an alkaline agent, which may be potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, preferably potassium carbonate. . In some embodiments, the molar ratio of the compound of Formula I to the ethylating agent is from 1:0.5 to 1:2, preferably from 1:1 to 1:1.5. In some embodiments, the ethylating agent can be It is selected from a halogenated ethane, preferably 1-chloroethane, 1-bromoethane or 1-iodoethane, and further preferably 1-bromoethane.

A further aspect of the application provides the use of a compound of formula III in the preparation of a Plast.

In yet another aspect, the present application provides a method for preparing Apster, comprising the following steps:

(a) reacting a compound of formula III with a methyl sulfinate to provide a compound of formula IV;

(b) a compound of formula IV is reductively aminated to give a compound of formula V;

(c) reacting a compound of formula V with compound B to provide a compound of formula VI;

(d) reacting a compound of the formula VI with 3-acetamidophthalic anhydride of the formula IX to give an aposta of the formula A,

Wherein L is a halogen, preferably Cl, Br or I, more preferably Cl or Br; B is an asymmetric acid selected from the group consisting of L-aspartic acid, L-pyroglutamic acid or N-acetyl-L- bright Amino acid, preferably N-acetyl-L-leucine.

In some embodiments, the molar ratio of the compound of formula III to methyl sulfinate in step (a) is from 1:0.5 to 1:2, preferably from 1:1.2 to 1:1.5. In some embodiments, the methyl sulfinate salt in step (a) is preferably sodium methyl sulfinate. In some embodiments, the compound of formula III and the methyl sulfinate salt in step (a) can be reacted in a solvent, which may be selected from the group consisting of methanol, acetonitrile, ethanol, and the like, preferably ethanol.

In some embodiments, the reductive amination in step (b) may comprise ammonium formate reduced amine Ammonia, hydrogen and ammonia reductive amination or Leuckart reaction, preferably ammonium formate reductive amination.

In some embodiments, the reaction described in step (c) can be carried out in an alcohol solvent, preferably methanol.

In some embodiments, the reaction described in step (d) can be carried out in acetic acid.

In some embodiments, the compound of formula IX in step (d) is prepared by reacting a compound of formula VII with compound C to form a compound of formula VIII, which is then reacted with acetic anhydride.

In some embodiments, the compound C is selected from the group consisting of hydrochloric acid, sulfuric acid or hydrobromic acid, preferably concentrated hydrochloric acid, further preferably 37% concentrated hydrochloric acid.

In some embodiments, the compound of formula III described in step (a) is prepared by the process of the preparation of a compound of formula III as hereinbefore described.

The present application also provides a process for the preparation of a compound of formula IX comprising the steps of reacting a compound of formula VII with compound C to form a compound of formula VIII, and reacting the compound of formula VIII with acetic anhydride to provide a compound of formula IX,

In the present application, the ethanol is anhydrous ethanol unless otherwise specified.

In the present application, h refers to hours.

In the present application, EA means ethyl acetate.

In the present application, DMF means N,N-dimethylformamide.

In the present application, NBS means N-bromosuccinimide; NIS means N-iodosuccinimide.

In the present application, 37% hydrochloric acid means that the mass ratio of the hydrogen chloride solute to the hydrochloric acid solution is 37%.

In the present application, dichlorohydantoin refers to 1,3-dichloro-5,5-dimethylhydantoin.

The preparation method of the apster provided by the present application can avoid the use of n-butyl lithium n-hexane solution. This not only reduces the production cost, but also facilitates the operation process, and greatly improves the safety in industrial production, and is more suitable for industrial continuous production. In the preparation method provided by the present application, the yield of 3-acetylaminophthalic anhydride is increased to 81%, and the yield is high, which is extremely suitable for industrial production of Apster.

detailed description

The technical solutions of the present application are further described below in conjunction with specific embodiments, but the scope of protection of the present application is not limited to the scope of the embodiments described.

The reagents used in the examples are all commercially available products.

Synthesis of the compound of formula II of Example 1

The compound of formula I (0.25 mol), DMF (400 mL), potassium carbonate (0.25 mol) and 1-bromoethane (0.30 mol) were placed in a 1 L four-necked flask and reacted at 25 ° C for 4 h. The reaction mixture was poured into water (600 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated White solid. It was beaten with n-hexane (100 mL) for 10 min, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give 42 g of compound of formula II as a white solid.

^{1 H NMR (400MHz, DMSO)} δ: 7.62 (dd, J = 8.4,2.0Hz, 1H), 7.43 (d, J = 1.9Hz, 1H), 7.07 (d, J = 8.4Hz, 1H), 4.07 ( q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 2.53 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H).

Synthesis of the compound of the formula III-1 of Example 2

The compound of the formula II (25 mmol), phenyltrimethylammonium tribromide (25 mmol), tetrahydrofuran (10 mL) and methanol (10 mL) were added to the reaction flask, and reacted at 20 ° C for 1 h, and the solvent was evaporated under reduced pressure. 50 mL of each of EA and EA, extracting and separating, and extracting with EA (50 mL×2), and absorbing the organic phase, washing with an appropriate amount of 2M aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was dried under vacuum at 40 ° C for 5 h to give 6.0 g of Compound III Compound Compound

^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 7.62 (dd, J = 8.4,2.0Hz, 1H), 7.56 (d, J = 2.0Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 4.42 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.97 (s, 3H), 1.51 (t, J = 7.0 Hz, 3H).

Synthesis of the compound of the formula III-2 of Example 3

The compound of the formula II (50 mmol), methanol (100 mL) and p-toluenesulfonic acid (25 mmol) were added to a 250 mL four-necked flask, and an ice water bath was used at 5 ° C, and dichlorohydantoin (total 37.5 mmol) was added in three portions. The temperature control is below 10 °C. After the addition, the temperature was naturally raised to 25 ° C, the system was clarified, and the reaction was carried out for 15 h to precipitate a white solid. The solvent was evaporated under reduced pressure, and the residue was combined with water and EtOAc (100 mL). The combined organic layers were washed with EtOAc EtOAc m. It was washed with 2 mL of EA, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give 4.7 g of the compound of formula III-2 as a white solid.

^{1 H NMR (400MHz, DMSO)} δ: 7.65 (dd, J = 8.5,2.0Hz, 1H), 7.46 (d, J = 2.0Hz, 1H), 7.10 (d, J = 8.5Hz, 1H), 5.13 ( s, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H).

Synthesis of the compound of the formula III-3 of Example 4

The compound of formula II (50 mmol), DMF (100 mL) and NIS (75 mmol) were added to a 250 mL four-necked flask and stirred at room temperature for 15 h. The reaction system was added to 100 mL of water, and the mixture was combined with EtOAc (50 mL, EtOAc). It was washed with 2 mL of EA, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give 7.7 g of compound of formula III-3 as a white solid.

MS M/Z: 321 (M + 1).

Synthesis of the compound of the formula IV of Example 5

The compound of the formula III-2 (34.6 mmol), ethanol (160 mL) and sodium methylsulfinate (52 mmol) were placed in a 250 mL four-necked flask, and refluxed for 15 h. The solvent was evaporated under reduced pressure. The mixture was shaken, and the mixture was combined with methylene chloride (50 mL×3). It was washed with 2 mL of EA, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give 9.1 g of compound of formula IV as a white solid.

^{1 H NMR (400MHz, DMSO)} δ: 7.75 (dd, J = 8.5,2.0Hz, 1H), 7.50 (d, J = 2.0Hz, 1H), 7.12 (d, J = 8.5Hz, 1H), 5.05 ( s, 2H), 4.10 (q, J = 6.9 Hz, 2H), 3.88 (s, 3H), 3.14 (s, 3H), 1.36 (t, J = 6.9 Hz, 3H).

Synthesis of the compound of formula IX of Example 6

The compound of the formula VII (0.55 mol) and 37% concentrated hydrochloric acid (500 mL) were added to a 1 L single-necked flask, and the mixture was stirred at 25 ° C for 15 h, and the water was evaporated under reduced pressure, and the mixture was stirred for 10 min with tetrahydrofuran (300 mL). The white solid was obtained in an amount of 120 g, and the Karl Fischer method was used to determine a water content of 0.5%. Add this solid to a 2 L four-necked flask, add acetic anhydride (1.2 L), react at 100 ° C for 15 h, distill off acetic anhydride under reduced pressure, cool, add 200 mL of methyl tert-butyl ether to the residue, beat for 10 min, filter, use The solid was washed with 20 mL of methyl tert-butyl ether, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give 94 g of the compound of formula IX as a white solid.

^{1 H NMR (400MHz, DMSO)} δ: 9.85 (s, 1H), 8.42 (d, J = 8.3Hz, 1H), 7.95 (dd, J = 8.3,7.4Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 2.22 (s, 3H).

Synthesis of the compound of the formula V of Example 7

The compound of formula IV (5mmol), ammonium formate (50mmol), methanol (40mL), water (4mL) and Pd/C (0.5g) were sequentially added to a 100mL single-mouth bottle, refluxed for 15h, filtered, 10mL methanol washed filter residue, filtrate The solvent was evaporated under reduced pressure and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Compound of formula V, yield 87.8%.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 7.03-6.82 (m, 3H), 4.63 (dd, J = 9.4,3.1Hz, 1H), 4.13 (q, J = 7.0Hz, 2H), 3.89 (s, 3H), 3.31 (ddd, J = 17.2, 14.1, 6.3 Hz, 2H), 2.93 (s, 3H), 1.49 (t, J = 7.0 Hz, 3H).

Synthesis of the compound of the formula VI-1 of Example 8

The compound of formula V (0.1 mol) and methanol (200 mL) were added to the reaction flask, and the solution was refluxed, and N-acetyl-L-leucine (0.06 mol) was added in portions. A large amount of solid was produced, refluxed for 1 hour, and then naturally cooled. The mixture was stirred at 25 ° C for 1 h, filtered, and the filter cake was dried under vacuum at 40 ° C for 5 h to give a white solid (22.6 g). The solid and 180 mL of methanol were added to the reaction flask, refluxed for 1 h, cooled to 25 ° C, stirred for 1 h, filtered, filter cake Drying at 40 ° C for 5 h under vacuum gave 18 g of the compound of formula VI-1 as a white solid, dried in vacuo at 40 ° C for 5 h, ee: 98.6%.

HPLC (n-hexane: isopropanol: diethylamine: trifluoroacetic acid = 90:10:0.2:0.5), Dasai Road AD-H 4.6*250mm, 5um, 1.0mL/min, 240nm: 9.3min (S-different Construct, 99.3%), 6.2 min (R-isomer, 0.7%).

Synthesis of Compound A of Example 9

The compound of the formula VI (40.08 mmol), the compound of the formula IX (42.06 mmol) and acetic acid (500 mL) were added to the reaction flask, and the reaction was refluxed for 15 h. The solvent was evaporated under reduced pressure. Extracted with EA (100 mL×2), EtOAcjjjjjjjjjjjjjjjjj Then, 70 mL of absolute ethanol was added, refluxed for 15 min, naturally cooled, stirred and crystallized at 25 ° C for 3 h, filtered, washed with a small amount of anhydrous ethanol, and the filter cake was dried under vacuum at 40 ° C for 5 hours to obtain 11.1 g of Compound A as a white solid. 60.3%, HPLC: 99.7%, single impurity less than 0.1%, ee: 98.6%.

HPLC (n-hexane: isopropanol = 80:20), Dasai Road AD-H 4.6*250 mm, 5 um, 1.0 mL/min, 230 nm: 47.7 min (S-isomer, 99.3%), 51.2 min (R- Isomer, 0.7%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ: 9.48 (s, 1H), 8.78 (d, J = 8.4Hz, 1H), 7.76-7.59 (m, 1H), 7.51 (d, J = 7.3Hz, 1H) , 7.20–7.06 (m, 2H), 6.87 (d, J = 8.8 Hz, 1H), 5.89 (dd, J = 10.5, 4.4 Hz, 1H), 4.58 (dd, J = 14.3, 10.6 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 3.74 (dd, J = 14.4, 4.4 Hz, 1H), 2.89 (s, 3H), 2.28 (s, 3H), 1.49 (t , J = 7.0 Hz, 3H).

The above general description of the invention and the description of the specific embodiments thereof are not to be construed as limiting the invention. In accordance with the disclosure of the present application, those skilled in the art can increase or decrease the disclosed technical features in the above general description or/and specific embodiments (including embodiments) without departing from the inventive constituent elements involved. Or a combination, forming other technical solutions belonging to the invention. The scope of protection of the invention disclosed in this application shall be determined by the scope of protection defined by the claims.

Claims

a compound of formula III,

Wherein L is a halogen, preferably Cl, Br or I, more preferably Cl or Br.
A process for the preparation of a compound of formula III comprising the steps of reacting a compound of formula II with a halogenating reagent to provide a compound of formula III,

Wherein L is a halogen, preferably Cl, Br or I, more preferably Cl or Br.
The production method according to claim 2, wherein the halogenating agent is selected from the group consisting of dichlorohydantoin, liquid bromine, N-bromosuccinimide, N-iodosuccinimide or phenyltrimethyl. Ammonium tribromide, preferably dichlorohydantoin or phenyltrimethylammonium tribromide; and/or the molar ratio of the compound of formula II to the halogenating agent is from 1:0.5 to 1:2, preferably 1:0.75 ~1:1.
The process according to claim 2 or 3, wherein the compound of the formula II is obtained by reacting a compound of the formula I with an ethylating agent,
The process according to claim 4, wherein the compound of the formula I and the ethylating agent are reacted in the presence of an alkaline agent, preferably potassium carbonate, sodium carbonate, potassium hydroxide or hydrogen. Sodium oxide, more preferably potassium carbonate; and/or a molar ratio of the compound of formula I to the ethylating agent of from 1:0.5 to 1:2, preferably from 1:1 to 1:1.5; and/or The ethylating agent is selected from the group consisting of haloethanes, preferably 1-chloroethane, 1-bromoethane or 1-iodoethane, further preferably 1-bromoethane.
The use of a compound of formula III in the preparation of apster,
The preparation method of Apster includes the following steps:

(a) reacting a compound of formula III with a methyl sulfinate to provide a compound of formula IV;

(b) a compound of formula IV is reductively aminated to give a compound of formula V;

(c) reacting a compound of formula V with compound B to provide a compound of formula VI;

(d) reacting a compound of the formula VI with 3-acetamidophthalic anhydride of the formula IX to give an aposta of the formula A,

Wherein L is a halogen, preferably Cl, Br or I, more preferably Cl or Br; B is selected from L-aspartic acid, L-pyroglutamic acid or N-acetyl-L-leucine, preferably N -Acetyl-L-leucine.
The preparation method according to claim 7, wherein:

The molar ratio of the compound of the formula III and the methylsulfinate in the step (a) is from 1:0.5 to 1:2, preferably from 1:1.2 to 1:1.5; and/or the methylsulfinic acid The salt is sodium methylsulfinate; and/or the compound of formula III and the methylsulfinate are reacted in a solvent, preferably selected from the group consisting of methanol, acetonitrile or ethanol, more preferably ethanol.
The preparation method according to claim 7 or 8, wherein:

The reductive amination in step (b) is ammonium formate reductive amination, hydrogen and ammonia reductive amination or Leuckart reaction, preferably ammonium formate reductive amination.
The production method according to any one of claims 7 to 9, wherein:

The reaction described in the step (c) is carried out in an alcohol solvent, preferably methanol.
The production method according to any one of claims 7 to 10, wherein:

The reaction described in step (d) is carried out in acetic acid.
The process according to any one of claims 7 to 11, wherein the compound of the formula IX is prepared by reacting a compound of the formula VII with a compound C to form a compound of the formula VIII, which is then reacted with acetic anhydride.
The process according to claim 12, wherein the compound C is selected from the group consisting of hydrochloric acid, sulfuric acid or hydrobromic acid, preferably concentrated hydrochloric acid, further preferably 37% concentrated hydrochloric acid.
The process according to any one of claims 7 to 13, wherein the compound of the formula III in the step (a) is produced by the process according to any one of claims 2-5.
A process for the preparation of a compound of formula IX comprising the steps of reacting a compound of formula VII with compound C to form a compound of formula VIII, and reacting the compound of formula VIII with acetic anhydride to provide a compound of formula IX,
The process according to claim 15, wherein the compound C is selected from the group consisting of hydrochloric acid, sulfuric acid or hydrobromic acid, preferably concentrated hydrochloric acid, further preferably 37% concentrated hydrochloric acid.