WO2008134923A1 - A preparation method of thiol derivative as side chain intermediate for synthesis of carbapenem derivative - Google Patents

Abstract

A preparation method of thiol derivative as side chain intermediate for synthesis of carbapenem derivative. The method is starting with trans-4-hydroxy-L-proline derivative as starting material, following by one-pot method that 2-carbonyl group is protected, 4-hydroxy is protected and 2-postion is substituted to obtain 2-amide proline derivative, then 4-postion is substituted and 4-postion is hydrolyzed in the presence of base to obtain thiol side chain derivative as important intermediate for Meropenem. The present method is simple, without separating intermediates, with high yield and easy to operate and has advantages over the prior patent methods. It is suitable for industrial production.

Description

 Preparation method of perampanoid branched-chain intermediate-monothiol derivative

 The present invention relates to the field of organic chemistry and medicinal chemistry, and in particular, to a method for preparing a thiol derivative of a medicinal branched intermediate of piran. Background technique

Peron (carbampenal) drugs such as imipenem, meropenem and biapenem have good antibacterial activity against many resistant bacteria, especially for B-type enzymes. A unique inhibitor of lactamase inhibition. (2S, 4S)-Substituted carbamoyl-4-mercapto- 1-(N-substituted) pyrrolizole (i) is an important branched intermediate of piranol drugs such as meropenem.

Among them, a lower decyloxycarbonyl group, a halogenated decyloxycarbonyl group, a fluorenyloxycarbonyl group having a aromatic diameter, and a trimethylsilyl group, and R ₄ and R ₅ represent the same or different hospitals containing d-Cs carbon atoms. a olefin group having a C ₃ - C ₄ carbon atom, a aryl group containing a - ( ₃ hydrocarbon group substituted).

^ can be tert-butoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trimethyl A silyl group or a tert-butyldimethylsilyl group; and R ₂ may be an ethoxycarbonyl group, a tert-butoxycarbonyl group, an isopropoxycarbonyl group, a methanesulfonyl group or a p-toluenesulfonyl group.

R ₄ and R ₅ may be the same or different and include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, propenyl, butenyl, phenyl, substituted phenyl, pyridyl, 2 Pyridinemethyl, 3-pyridylmethyl, 4-pyridylmethyl.

另一种方法是以 trans- 4-羟基 -L-脯胺酸为原料， 经吡咯环上的氨基保 护， 2位羧基直接与仲胺反应得到酰胺，再通过 4位取代，水解得化合物（i )， 其合成路线如下式 2: Sumitomo pharmaceuticals Co., Ltd reported the synthetic route of two compounds (i) [Makoto S-touch gawa, β-lactam compounds [P], US 4943569, 1990-7-24]. The first method is to use t ns-4-hydroxy-L-proline as the raw material, protected by the amino group on the pyrrole ring, the 2-position carboxyl group is protected to form an ester, the 4-position hydroxyl group is substituted to obtain a vapor, and then the second position is hydrolyzed. The carboxylic acid, the amidation, and the 4-position hydrolysis are carried out in a total of 6 steps to obtain the compound (i), and the reaction route is as follows:

Another method is to use trans- 4-hydroxy-L-proline as a raw material, protected by an amino group on a pyrrole ring, and the 2-position carboxyl group is directly reacted with a secondary amine to obtain an amide, and then substituted at the 4-position to obtain a compound (i). ), its synthetic route is as follows:

式 2

Equation 2

Patent W09902513 mentions another route which uses amino-protected trans-4-hydroxy-L-proline as a raw material, is protected by a 2-carboxyl group, a 4-hydroxyl group, is ring-closed, and is ring-opened to obtain a compound (i). The synthetic route is as follows:

 Formula 3 Summary of the Invention

The object of the present invention is to provide a preparation method of a perylene-based drug branched-chain intermediate-thiol derivative, and the synthetic route of the preparation method is as shown in formula 4:

 (v)

 (·)

The technical solution of the method of the invention is:

 ^

 A method for preparing a peronal drug branched-chain intermediate monothiol alcohol derivative, characterized in that the method comprises the following steps:

 A), using L-proline derivative (ii) as a raw material, and protecting the compound (iii) by a carboxyl group in the presence of an organic base:

VN COORi

B), compound (iii) is reacted with methylsulfonyl chloride to give compound (iv):

 0. The compound (iv) is reacted with dimethylamine hydrochloride to obtain a compound (V)

 D), reacting compound (v) with potassium thioacetate or thioacetic acid to obtain compound (vi)

其中： 表示酰基化合物。 E), the compound (vi) is hydrolyzed under basic conditions to obtain a thiol derivative (i) of a perindanic branched intermediate.

Wherein: represents an acyl compound.

 The preparation method of the peronic drug branched-chain intermediate-monothiol derivative is characterized in that:

 From the L-proline derivative (ii) to the compound (V), the compound (iii) and the compound (iv) are isolated, and the compound (v) is obtained in a one-pot method. The first two steps use a one-pot method to make the compound (iii) and the compound (iv) directly obtain the compound (v) without isolation, which simplifies the operation and reduces the production cost.

 The preparation method of the peronic drug branched-chain intermediate-monothiol derivative is characterized in that: from the compound (V) to the target (i), the compound (vi) is directly subjected to hydrolysis without drying treatment. The desired product thiol derivative (i) is obtained.

 The preparation method of the peronic drug branched-chain intermediate-monothiol derivative is characterized in that:

 The L-proline derivative (ii) is protected by a carboxyl group under the catalysis of an organic base to obtain a compound (iii) wherein the ratio of the organic base to the L-proline derivative (ii) is 1 to 4:1. Temperature is - 20 to 30 ° C;

 The compound (iii) is obtained by directly adding methylsulfonyl chloride for 0.4 to 3 hours without isolation to obtain a compound (iv) wherein the ratio of the methylsulfonyl chloride to the raw material L-proline derivative (ii) is 0.5 to 2 : 1, the reaction temperature is -35 ° C - 10 ° C;

 Compound (iv) is reacted with dimethylamine hydrochloride for 0.5 to 6 hours to obtain compound (V), wherein the ratio of dimethylamine hydrochloride to the starting material L-proline derivative (ii) is 0.5 to 2: 1, and the reaction temperature is - 35 °C - 10 °C;

 Compound (V) is reacted with potassium thioacetate or thioacetic acid in an aprotic solvent at 25 to 60 ° C for 10 to 25 hours to obtain compound (vi); wherein potassium thioacetate or thioacetic acid and compound (V) The ratio is 0.5~3: 1

 The compound (vi) is hydrolyzed in a basic alcohol solution to obtain the desired product thiol derivative (i), and the reaction temperature is -35 to 35° (the alkali solution concentration is 0.1 to 5 mol/L).

The preparation method of the peronic drug branched-chain intermediate-monothiol derivative is characterized in that - The organic base used in the step A is triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine, tri-n-propylamine or tri-n-butyl amine;

 The preparation method of the peronic drug branched-chain intermediate-monothiol derivative, characterized in that - the aprotic solvent in step D is hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethyl methoxide Acetylamine, acetonitrile, dimethyl sulfoxide or pyridine.

 The preparation method of the peronic drug branched-chain intermediate-monothiol derivative is characterized in that:

 Step The alkaline solution in the crucible is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, sodium methoxide in methanol or ethanol. The beneficial effects of the present invention are as follows: A method for preparing a peronic drug branched-chain intermediate-thiol derivative is provided, and the first two steps of the preparation method adopt a one-pot method to make the compound (iii) and the compound (iv) need not be used. Separation, direct compound (v), simplifies operation and reduces production costs. At the same time, by changing the process route, the product is easier to purify and the yield is improved. Compared with the prior patent literature, the invention has simple method, the intermediate does not need to be separated, the yield is high, the operation is easy, and the method is suitable for large-scale production. detailed description

 The invention is further illustrated by the following examples.

 Example 1 Preparation of (2S, 4R) 1-(p-nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoacyl)-4-methanesulfonylpyrrole

 Add dichloromethane (300 ml) to a 500 ml reaction flask, stir, add N-p-nitrobenzyloxycarbonyl-4-S-hydroxyproline (20 g, 64.5 mmol), cool to -20 ° C, add Triethylamine (19.5 g, 193 mmol), stirred for 5 minutes, isopropyl chloroformate (8.2 g, 67. 2 mmol) was added dropwise, about 1 hour dropwise, and after 5 hours of reaction, the temperature was further lowered to -35 ° C. Then, methanesulfonyl chloride (14.7 g, 128 mmol) was added in portions, and stirring was continued for 3 hours, then dimethylamine hydrochloride (5.3 g, 64. 5 mmol) was added, and the reaction was stirred for 6 hours, then 120 ml of water was added, and extracted. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, then ethyl acetate was dissolved, and the solid was precipitated with petroleum ether, filtered, and dried to obtain intermediate (2S, 4R) 1- (Benzyloxycarbonyl)-2-(N,N-dimethylaminoacyl)-4-carboxysulfonylpyrrole (21. lg, 78.7%).

Example 2 (2S, 4S) 1-(p-Nitrobenzyloxycarbonyl)-2-(N,N-dimethylamino Preparation of acyl)-1,4-mercaptopyrrolidine

 In a 250 ml reaction flask was added DMF (150 ml), (2S, 4R) 1_p-nitrobenzyloxycarbonyl-2-(N,N-dimethylaminoacyl)-4-S-methanesulfonate (15. 0g, 36iranol), stirred and dissolved, added potassium thioacetate (4.3 g, 37.7 mmol), reacted at 25 ° C for 10 hours, then quickly poured into 1000 ml of ice water, stirred to precipitate a solid, filtered to obtain a wet product .

 0〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3〜3~3~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Left and right, layered, the organic layer was evaporated to dryness under reduced pressure, dissolved in methanol, and then solidified with petroleum ether, filtered and dried to give (2S, 4S) 1- (p-nitrobenzyloxycarbonyl) -2- (N , N-Dimethylaminoacyl)-4-indolylpyrrole (12. 2g, 95%).

 Example 3 Preparation of (2S, 4R) 1-(p-nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoyl)-4-methanesulfonylpyrrole

 Add dichloromethane (250 ml) to the flask, stir, add N-p-nitrobenzyloxycarbonyl-4-S-hydroxyproline (16.2 g, 52 匪ol), cool to 5 ° C, add two Isopropylethylamine (6.4 g, 55 ol), stirring for 5 to 10 minutes, dropwise addition of ethyl chloroformate 5. 7 g, 52. 8 paintings 1 ), about 1 hour dropwise, 2 hours after the reaction, adding dropwise Methanesulfonyl chloride (6 g, 52.2 mmol), stirring was continued for 1 hour after the addition, then dimethylamine hydrochloride (8.2 g, 100 mmol) was added, and the reaction was stirred for 2 hours, then 100 ml of water was added, and the layers were separated, and the organic layer was used. Drying with sodium sulfate, distilling off the solvent under reduced pressure, then adding ethanol, stirring and dissolving, adding petroleum ether to precipitate a solid, filtering, and drying to obtain intermediate ((2S, 4R) 1 (p-nitrobenzyloxycarbonyl) -2 - (N, N-Dimethylaminoacyl)-4-methylsulfonylpyrrole (17. 8 g, 82%).

 Example 4 Preparation of (2S, 4S) 1-(p-nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoyl)-4-indolylpyrrolidine

 In a 250 ml reaction flask was added DMF (120 ml), (2S, 4R) 1-p-nitrobenzyloxycarbonyl-(2-N,N-dimethylaminoacyl)-4-methanesulfonylpyrrole (13. 3 g, 31. 9 mmol), stirred and dissolved, added thioacetic acid (4.85 g, 63.8 mmol), and reacted at 60 ° C for 25 hours, then quickly poured into 1000 ml of ice water, and the precipitated solid was stirred and filtered to obtain a wet product.

 0〜3〜3〜3〜3~3~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Left and right, layered, the organic layer is steamed under reduced pressure, dissolved in methanol, and then added with petroleum ether to precipitate a solid, which is filtered and dried to give (2S, 4S) 1-(p-nitrobenzyloxycarbonyl)-2-(N , N-dimethylamino acyl)-4-mercaptopyrrole (9. 6g, 85%).

Example 5 (2S, 4R) 1-(p-Nitrobenzyloxycarbonyl)-2-(N,N-dimethylamino) Preparation of -4-methylsulfonylpyrrole

 Dichloromethane (300 ml) was added to a 500 ml reaction flask, stirred, and N-p-nitrobenzyloxycarbonyl-4-S-hydroxyproline (20 g, 64.5 leg ol) was added, and pyridine (20.3 g) was added at 30 °C. , 257 mmol), stirred for 10 minutes, t-butyl chloroformate (9.2 g, 67.6 mmol) was added dropwise, and the addition was completed in 0.5 to 1 hour. After maintaining the reaction at 30 ° C for 1 hour, the temperature was lowered to 10 ° C. Then, methanesulfonyl chloride (4. lg, 35.5 mmol) was added dropwise. After the addition was completed, stirring was continued for 0.4 hours, then dimethylamine hydrochloride (2.7 g, 33. lmmol) was added, and the reaction was stirred for 0.5 hour, then 120 ml of water was added, and the extract was extracted. The organic layer is dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure, then ethyl acetate is dissolved, and the solid is precipitated with petroleum ether, filtered, and dried to give intermediate (2S, 4R) 1- Benzyloxycarbonyl)-2-(N,N-dimethylaminoacyl)-4-methanesulfonylpyrrolidine (15.0 g, 56%).

 Example 6 Preparation of (2S, 4S) 1-(p-nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoyl)-4-mercaptopyrrole

 In the reaction flask was added DMSO (75 ml), (2S, 4R) 1_(p-nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoacyl)-4-methanesulfonylpyrrole (8. Lg, 19.5 mmol), stirred and dissolved, added potassium thioacetate (6.8 g, 58.7 ranol), and reacted at 40 ° C for 21 hours, then quickly poured into 600 ml of ice water, stirred to precipitate a solid, and filtered to obtain a wet product.

 Add the obtained wet product to 80 ml of dichloromethane, stir, then add 30 ml of 2 mol/L sodium ethoxide in ethanol, stir the reaction at 35 ° C for 50 minutes, then add dilute hydrochloric acid to adjust the pH to 2.5~3, The organic layer is evaporated to dryness under reduced pressure, dissolved in methanol, and then petroleum ether is added to precipitate a solid, which is filtered and dried to give (2S, 4S) 1-(p-nitrobenzyloxycarbonyl)-2-(N, N- Dimethylamino)-4-indolylpyrrole (3.9 g, 56.6%).

 Example 7 Preparation of (2S, 4R) 1-(p-nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoyl)-4-methylsulfonylpyrrole

Add methylene chloride (300 ml) to a 500 ml reaction flask, stir, add N-p-nitrobenzyloxycarbonyl-4-S-hydroxyproline (20 g, 64.5 mmol), add isopropyl at _5 °C Ethylamine (14.9g, 129 let ol), stir 5~: L0 clock, add ethyl chloroformate (7. lg, 65.5 draw 1), add 0.5~1 hour, add methyl sulfonate after 3 hours of reaction Acid chloride (9.9, 86.8 mmol), stirring was continued for 1.5 to 2 hours after the addition, then dimethylamine hydrochloride (5.4 g, 66 mmol) was added, and the reaction was stirred for 4 hours, then 120 ml of water was added, and the layers were separated, and the organic layer was treated with anhydrous sulfuric acid. Dry the sodium, distill the solvent under reduced pressure, then dissolve with ethyl acetate, add petroleum ether to precipitate a solid, filter, and dry to give intermediate (2S, 4R) 1 - (p-nitrobenzyloxycarbonyl)-2- (N, N-dimethylamino)-4-methanesulfonate pyrrolidine (22.5 g, Example 8 Preparation of (2S, 4S) 1-(p-Nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoyl)-4-indolylpyrrolidine

 In the reaction flask was added acetonitrile (100 ml), (2S, 4R) 1-(p-nitrobenzyloxycarbonyl)-2-(N,N-dimethylaminoacyl)-4-methanesulfonylpyrrole (15 g) , 36 mmol), stirred and dissolved, added potassium thioacetate (2. lg, 18. 4 mmol), and reacted at 35 ° C for 14 hours, then quickly poured into 800 ml of ice water, and the precipitated solid was stirred and filtered to obtain a wet product.

 5〜 The pH is adjusted to 2. 5~ Add the diluted hydrochloric acid to adjust the pH value to 2. 5~ 3, layering, the organic layer is evaporated to dryness under reduced pressure, dissolved in methanol, then added to petroleum ether to precipitate solids, filtered, and dried to give (2S, 4S) 1-(p-nitrobenzyloxycarbonyl)-2- ( N, N-dimethylamino acyl)-4-mercaptopyrrole (9.3 g, 73%).

Claims

Rights request  A method for preparing a perindyl-based drug branched-chain intermediate-thiol derivative, characterized in that the method comprises the steps of: A), using L-proline derivative (ii) as a raw material, and protecting the compound (iii) by a carboxyl group in the presence of an organic base:

B), compound (iii) is reacted with methylsulfonyl chloride to give compound (iv):

C), reacting compound (iv) with dimethylamine hydrochloride to obtain compound (V)

 D), reacting compound (v) with potassium thioacetate or thioacetic acid to obtain compound (vi)

 E), the compound (vi) is hydrolyzed under basic conditions to obtain a mercaptan (i) of a perindanic branched intermediate.

Wherein: Ri represents an acyl compound.  The method for preparing a peronal drug branched-chain intermediate-monothiol derivative according to claim 1, which is characterized in that: From L-proline derivative (ii) to compound (v), compound (iii) and compound (iv) The compound (v) is obtained in a one-pot method without isolation.  The method for preparing a peronic drug branched-chain intermediate-monothiol derivative according to claim 1, wherein: from the compound (V) to the target (i), the compound (vi) is not The drying treatment is carried out directly to obtain the desired product thiol derivative (i).  The method for preparing a peronal drug branched-chain intermediate-monothiol derivative according to claim 1 or 2 or 3, which is characterized in that:  The L-proline derivative (ii) is protected by a carboxyl group under the catalysis of an organic base to obtain a compound (iii) wherein the ratio of the organic base to the L-proline derivative (ii) is 1 to 4:1. The temperature is -20~ 30 °C;  Obtaining the compound (iii) without isolation, directly adding methylsulfonyl chloride for 0.4 to 3 hours to obtain a compound (iv) wherein the ratio of the methylsulfonate to the raw material L-proline derivative (ii) is 0.5 to 2 : 1, the reaction temperature is -35 ° C -10 ° C;  Compound (iv) is reacted with dimethylamine hydrochloride for 0.5 to 6 hours to obtain compound (v), wherein the ratio of dimethylamine hydrochloride to the starting material L-proline derivative (ii) is 0.5 to 2: 1, and the reaction temperature is -35 °C - 10 °C;  Compound (v) is reacted with potassium thioacetate or thioacetic acid in an aprotic solvent at 25 to 60 ° C for 10 to 25 hours to obtain compound (vi); wherein potassium thioacetate or thioacetic acid and compound (V) The ratio is 0.5~3: 1  The compound (vi) is hydrolyzed in a basic alcohol solution to obtain a target product thiol derivative (i), a reaction temperature of -35 to 35 ° C, and an alkali solution concentration of 0·1 to 5 mol/L.  The method for producing a perylene-based drug branched-chain intermediate-thiol derivative according to claim 1 or 2 or 3 or 4, which is characterized in that:  The organic base used in the step A is triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine, tri-n-propylamine or tri-n-butyl Butylamine  The method for producing a perindane-based branched-chain intermediate-thiol derivative according to claim 1 or 2 or 3 or 4 or 5, which is characterized in that:  The aprotic solvent in step D is N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide or pyridine.  The method for producing a perindole-based branched-chain intermediate-thiol derivative according to claim 1 or 2 or 3 or 4 or 5 or 6, which is characterized in that:  The alkaline solution in the step E is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, sodium methoxide in ethanol or methanol.