WO2012027951A1

WO2012027951A1 - An intermediate used for preparation of imipenem medicine, a preparation method and use thereof

Info

Publication number: WO2012027951A1
Application number: PCT/CN2011/001365
Authority: WO
Inventors: 张工; 张艳丽
Original assignee: 上海巴迪生物医药科技有限公司
Priority date: 2010-09-02
Filing date: 2011-08-16
Publication date: 2012-03-08
Also published as: CN101973915A; CN101973915B

Abstract

The invention relates to an intermediate used for preparation of imipenem medicine, a preparation method and use thereof. The said intermediate is shown in the structure of formula (I), wherein R¹ is C₁- C₃ lower alkyl, nitryl, halogen, or hydrogen substituted at any position; R² is aryl, alkyl or arylalkyl; the said aryl, alkyl, or arylalkyl has or has not substituent group. The intermediate is prepared by reacting aniline with sulfuryl chloride, and then reacting the product with 2-bromo-propionyl bromide in the presence of organic base. The intermediate can be used in the synthesis of carbapenems i.e. the key intermediate of imipenem beta-methylazetidin-2-one (4BMA). The method has the advantages of simple process, cheap and easily-available raw materials, low cost, recycling of precursor after being recovered, high stereo-selectivity and yield.

Description

Intermediate for synthesizing Pein drugs and preparation method and application thereof

The invention relates to an intermediate for synthesizing a Pein drug, a preparation method and application thereof.

Background technique

Carbapenem antibiotics (ie, Peinan) are a new class of β-lactam antibiotics, which are known for their broad antibacterial spectrum and strong antibacterial activity. The key intermediate used in the main ring of synthetic Penin is β-methylazetidin- ₂ -one (4-ΒΜΑ). The introduction of the C-Ιβ-methyl group in 4-BMA greatly enhances the stability of the final product of the Pein-derived drug against renal dehydropeptidase (DHP-I) without the need to associate with the DHP-I inhibitor. The drug is used without affecting its antibacterial activity. The intermediate 4-BMA was synthesized from the intermediate 4-acetoxyazetidinone (abbreviated as 4AA), and then the C-Ιβ methyl structure was introduced via the intermediate 4-BMA.

The current synthesis of 4-BMA can be summarized into two technologies.

1) The terminal olefin compound is first reacted by 4AA, and the double bond is further introduced into the β-methyl group by asymmetric hydrogenation to obtain 4-anthracene, as in U.S. Patent No. 5,310,897, U.S. Patent No. 4,833,324, and European Patent Publication No. 230,792, and the like. The reaction formula is as follows:

In this method, the asymmetric hydrogenation reaction is relatively simple, but the preparation of the terminal olefinic compound is relatively difficult. 2) The condensation of 4AA and the enol by aldol condensation (Aldol condensation) or the Revelsky reaction (Reformatsky) Reaction) to give 4-BMA. In order to obtain a highly stereoselective 1-configuration of the 1-methyl compound, most Aldd condensation reactions rely on compounds having a particular cyclic structural auxiliary group such as 2-oxazolidinone, such as 1,3 -oxazole-2. -thione, 1,3-thiazole-2-thione, as described in U.S. Patent Nos. 4,791,207, 5,104,984, and European Patent Publication No. EP 197432. The preparation of the target product by the cyclic structural compound having such an auxiliary group is very expensive because of the poor availability of the compound and the complicated preparation process. Further, an example of 4-BMA is obtained by the Reformatsky reaction, such as J. Org. Chem. 1997, 62, 2877-2884 and Japanese Patent Publication JP06065195. The reaction formula is as follows:

The yield and stereoselectivity of the 4-BMA prepared in the above examples are largely dependent on the substituent on the benzoxazine. The 4-BMA obtained by the Reformatsky reaction also needs to rely on a special ring-assisted structure to obtain good results, and the requirements for the ring structure are harsh.

Summary of the invention

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the deficiencies of the prior methods described above and to provide a novel synthetic piranoid which is represented by the following formula (I):

Wherein R ¹ represents a lower azeohydrocarbyl group, a nitro group, a halogen, a hydrogen element or the like substituted at an optional position; R ² is an aryl group, a fluorenyl group or an aryl group, the aryl group, the alkyl group or the aryl group The thiol group may also have a substituent.

A method for preparing a compound of formula (I), comprising the steps of:

Reacting R ² S0 ₂ C1 (IV) with a compound of formula (III) in the presence of an organic base to form a compound of formula (V); The compound of formula (V) is reacted with 2-bromopropionyl bromide in the presence of an organic base to form a compound of formula (I), a novel compound which synthesizes a 4-BMA intermediate.

The reaction route is as follows -

Wherein R ² S0 ₂ C1 is a sulfonyl chloride compound, R ² is an aryl group, a fluorenyl group or an aryl fluorenyl group, and the aryl group, fluorenyl group or aryl fluorenyl group may further have a substituent. R ¹ represents a d-C ₃ lower hydrocarbon group, a nitro group, a halogenated group or the like which is optionally substituted at a position.

The aryl group includes a phenyl group, a naphthyl group, a pyridyl group and the like.

The fluorenyl group is a lower hydrocarbon group of 〜0» such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

The aryl fluorenyl group includes, for example, a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, a pyridylmethyl group, and the like. The substituent carried by the aryl, mercapto or aralkyl group may be a halo group, a nitro group, an amino group or a cyano group such as a trifluoromethyl group, a trichloromethyl group, a methylamino group, an ethylamino group, a dimethylamino group, Diethylamine and the like. When it is an aryl group or an aryl group, the number of the substituents may be single or plural, and when the number of the substituents is plural, the substituents may be the same or different, and the substitution position may be in the case of a single substituent. At the 2-, 3- or 4-position of the phenyl ring of the aryl or aralkyl group, in the case of double substitution, 2,3-, 2 of the phenyl ring of the aryl or aryl fluorenyl group a point of 4-, 2,5-, 2,6-, 3,4- or 3,5-position and any phenyl ring on the aryl or aryl-indenyl group in the case of more than two substituents The point at which the location is acceptable. In the case of a double substitution in which a substituent is adjacent, the terminals of the two substituents may be bonded and this case includes the formation of a linked aliphatic ring in which a propylene group, a butylene group or the like is bonded, and a connection such as a methylene dioxy group thereof. Formation of a cyclic ether compound.

R ² preferably includes phenyl, tolyl, chlorophenyl, nitrophenyl, benzyl or methyl.

When R ¹ is a lower hydrocarbon group of 〜, including, for example, methyl, trifluoromethyl, trichloromethyl, ethyl, n-propyl, isopropyl, etc.; when R ¹ is a halogen group, Including fluorine atoms, chlorine atoms, and bromine atoms And iodine atoms and the like.

The compound of the formula (m) is used in an amount of 0.8 to 1.5 equivalents based on the amount of the compound of the formula (IV); the amount of the organic base is 1.0 to 1.5 equivalents based on the amount of the compound of the formula (ΙΠ), and the organic base may be selected from pyrimidine or imidazole. , 2,6-lutidine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine, dimethylamine, pyridine, diphenylamine, etc.; the solvent used in the reaction is selected from the group consisting of dichloromethane One or more of 1,2-dichloroethane, dioxanthene, tetrahydrofuran, dimethoxyacetamidine, diisopropyl ether, ethyl acetate and acetonitrile. The reaction temperature is selected from -20 to 25 ° C, and the reaction time is from 20 to 60 min.

In the second step, the amount of 2-bromopropionyl bromide is 0.8 to 2.5 equivalents of the compound of the formula (V); the organic base is selected from pyrimidine, imidazole, 2,6-lutidine, 4-dimethylaminopyridine, triethyl b. The amine and diisopropylethylamine are used in an amount corresponding to 1.0 to 2.0 equivalents of the compound of the formula (V); the solvent used in the reaction is selected from the group consisting of dichloromethane, 1,2-dichloroethane, dioxanthene, One or more of tetrahydrofuran, dimethoxyethane, diisopropyl ether, ethyl acetate and acetonitrile. The reaction temperature is selected from -20 to 20 ° C, and the reaction time is from 0.5 to 24 hours.

The use of the above intermediate for the synthesis of a Pein drug is characterized in that it is used for the preparation of 4-BMA, and the specific method is as follows:

a) The compound (I) and the compound of formula (VI) 4AA are subjected to a Reformatsky reaction under the action of zinc powder to obtain a formula ( );

b) Formula (W) is hydrolyzed under basic conditions to give the key intermediate 4-BMA, while releasing the chiral reagent (V).

The reaction route is as follows:

(Π) (V)

In the condition of the above reaction - in the reaction step a), the amount of the compound of the formula (I) is 0.8 in an amount equivalent to the formula (VI) Equivalent; the amount of the metal catalyst is 2.0 to 4.0 equivalents based on the amount of the compound of the formula (VI), the metal catalyst may be selected from zinc powder, magnesium powder, etc.; the solvent used in the reaction is selected from the group consisting of dichloromethane, 1,2-dimethyl One or more of oxyethylene oxime, tetrahydrofuran, diethyl ether, and toluene. The reaction temperature is selected from 0 to 30 ° C, and the reaction time is from 1.5 to 4.0 h.

In the reaction step b), the basic condition may be lithium hydroxide, sodium hydroxide or the like, but a mild alkaline hydrolysis condition such as lithium hydroxide/hydrogen peroxide is preferred; the amount of the base is equivalent to the formula (V of 2.0) 4.0 equivalent; The reaction temperature is selected from -10 to 25 ° C, and the reaction time is from 4.0 to 8.0 h.

The above compound 4-BMA can be used for the synthesis of a carbapenem antibiotic (i.e., a Peinan), and the preparation process is as provided by the aforementioned known art.

The advantages of the present invention are as follows: 1. The synthesis of the novel compound in the present application is simple and easy to prepare; 2. The reactive group does not need to depend on a special cyclic structure, the raw material is cheap and easy to obtain, and the cost is low; 3. The former of the new compound The body can be reused after recovery; 4. The Reformatsky reaction of the new compound with 4AA, due to the presence of the methyl group in the R configuration at the α position on the side chain N, results in a methylation at the C1 position of the β configuration, which is dominant. Stereoselective enthalpy, good product yield.

DRAWINGS

Figure 1 is an infrared spectrum of the product of Example 2;

Figure 2 is a nuclear magnetic resonance spectrum of the product of Example 2;

Figure 3 is a nuclear magnetic resonance spectrum of the product of Example 6.

detailed description

In the following, the invention will be further illustrated by the following examples, which will be helpful in understanding the invention but not limiting the invention.

Example 1

1) Preparation of (R)-4-methyl-N-(l-phenylethylbenzenesulfonamide)

In a three-necked flask, 121 g (lmol) of (R)-methylbenzylamine, 500 ml of methylene chloride and 101 g (lmol) of triethylamine were stirred and cooled to 0 ° C, and 190 g (lmol) of TSC1 was added dropwise. The temperature is not higher than 10 ° C, The reaction was stirred at 0 to 10 ° C for 30 minutes. The organic phase was washed by separately adding 300 ml of 1 N hydrochloric acid and 300 ml of 5% sodium hydrogencarbonate and 300 ml of water. A large amount of crystals appeared by rotary evaporation, and then 300 ml of methanol was added to the concentrate, and most of the dissolution was caused by stirring and heating. Intermittently mix and cool down to 0'C, put into the freezer (or refrigerator) -15 °C

24 hours. Filter, wash with small amount of methanol, and dry in vacuo. Yield 240 g (yield 87%) of (R)-4-methyl

-N-(l-phenylethyl)benzenesulfonamide.

Mp 97~99. C,

[α] = +72° (c = 0.4, EtOH)

IR (KBr, cm' ¹ ): 3230, 3160-2850, 1590, 1450, 1310, 1155, 1080, 805, 765, 705, 670. 1H-NMR (200 MHz, CDC13): 6=1.39 (3H, d ), 2.36 (3H, s), 4.44 (1H, q), 5.48 (1H, d), 7.20-7.07(7H, m), 7.62(2H, m).

Example 2

2) Preparation of 2-bromo-N-((R)-1-phenylethyl)-N-p-toluenesulfonylpropionamide

50 g (0.182 mol) of (R)-4-methyl-N-(l-phenylethyl)benzenesulfonamide, 200 ml of dichloromethane and 31.2 g (0.3 mol) of triethylamine were added to the three-necked flask. 58.8 g (0.273 mol) of 2-bromopropionyl bromide was added dropwise while maintaining the temperature at 5 to 10 ° C, and the reaction was stirred at 5 to 10 ° C for 30 minutes, and further at room temperature for 17 hours. The organic layer was washed with saturated aqueous sodium hydrogen sulfate (150 ml) and brine (100 ml). 1-Phenylethyl)-N-p-toluenesulfonylpropionamide. The infrared spectrum and nuclear magnetic spectrum of the product are shown in Figures 1 and 2, respectively.

IR (KBr, cm' ¹ ) : 3062, 2979, 2924, 1703, 1596, 1496, 1447, 1357, 1147, 1121, 966.

1H-NMR (200 MHz, CDC 13): 1.58 (3H, m), 1.97 (3H, m), 2.43 (3H, d), 4.55 (1H, dd), 5.05 (1H, m), 7.12 (2H, m), 7.26-7.32(5H, m), 7.68(2H, m).

Example 3

3) Preparation of 2-bromo-N-(4-chlorophenylsulfonyl)-N-((R)-1-m-tolueneethyl)propanamide

The procedure was the same as in Example 1 and Example 2 except that 4-chlorobenzenesulfonyl chloride 13.5 g (0.1 mol) and R-1-m-toluethylamine 22.1 g (0.105 mol) were used to give a white powder. 34.6 g (yield 78.2%) 2-bromo-N-(4-chlorophenylsulfonyl)-N-((R)-1-m-toluethylethyl)propanamide.

Mp: 112~113°C

1H-NMR (200 MHz, CDC13): 1.58 (3H, m), 1.97 (3H, d), 2.35 (3H, s), 4.55 (1H, dd), 5.06 (1H, dd), 6.88-6.93 (3H , m), 7.09(1H, m), 7.61(2H, d), 7.74(2H, d)

Example 4

4) Preparation of 2-bromo-N-((R)-l-(3-nitrophenyl)ethyl)-N-p-toluenesulfonylpropionamide

The procedure was the same as in Example 1 and Example 2, except that 16.7 g (0.10 mol) of Rl-(3-nitrophenyl)ethylamine was used to obtain 40.0 g of a yellow oil (yield: 89.0%). Bromo-N-((R)-l-(3-nitrophenyl)ethyl)-N-p-toluenesulfonylpropionamide.

1H-NMR (200 MHz, CDC13): 1.58 (3H, m), 1.97 (3H, d), 2.43 (3H, s), 4.55 (1H, dd), 5.05 (1H, dd), 7.38 (2H, m ), 7.47-7.51(2H, m), 7.68(2H, m), 8.05(1H, s), 8.17(1H, m)

Example

The procedure was the same as in Example 1 and Example 2, except that 14.9 g (0.10 mol) of 4-nitrobenzenesulfonyl chloride and 22.50 g (0.105 mol) of Rl-(3-ethylphenyl)ethylamine were used. Obtained light yellow powder 35.2g (Yield 75.2%) 2-bromo-N-((R)-l-(3-ethylphenyl)ethyl)-N-(4-nitrophenylsulfonyl)propanamide.

Mp: 12 Bu 123 ° C

1H-NMR (200 MHz, CDC 13): 1.24 (3H, m), 1.58 (3H, m), 1.90 (3H, d), 2.59 (2H, m) _: 4.55 (1H, m), 5.05 (1H, Dd), 6.94-6.98(3H, m), 7.16(1H, m), 8.05(2H, d), 8.39 (2H, d).

Example 6

6) (R)-2-((2R,3S)-3-((R)-l-(tert-butyldimethylsilyloxy)ethyl)-4-oxoazinobutanone-2- Preparation of -N-((R)-l-phenethyl)-N-p-toluenesulfonylpropionamide

23.5 g (0.360 mol) of zinc powder was dissolved in 55 ml of THF, and heated under reflux for 30 to 40 mim. A solution of 35 g (0.122 mol) of 4AA in 55 ml of THF was slowly added dropwise at reflux temperature. After cooling, the reaction temperature was controlled at 20 to 25 ° C, and 70 g (0.199 mol) of 2-bromo-N-((R)-1-phenylethyl)-N-p-toluenesulfonylpropanamide in 87.5 ml of THF was added dropwise. The solution is controlled by high performance liquid to complete reaction. 6.0 g of diatomaceous earth was added to the reaction mixture, and the mixture was stirred for 5 min, filtered, and the filter cake was washed with 40 ml of THF, and filtrated to give 266 g of filtrate. 50 g of the filtrate was taken, 16 ml of toluene was added, and 25 g of a 10% saline solution was added thereto, and the mixture was stirred for 15 minutes, and then a 4N hydrochloric acid solution was added dropwise until the pH of the aqueous phase was 5.0. Static stratification, leaving the organic phase, ready for use. The NMR spectrum of the product is shown in Figure 3, yield 80%, β/α = 91: 9.

MP: 128~130°C

Ή-NMR (300 MHz, DMSO): 0.02 (6H, s), 0.87 (9H, s), 0.90 (3H, d), 0.96 (3H, d), 1.90 (3H, d), 2.46 (3H, s ), 3.07-3.11(lH, m), 3.61(1H, d), 3.94-3.97(lH, m), 5.70-5.74(lH, m), 7.22-7.48(5H, m), 7.45-7.48(2H , d), 7.85(2H, d), 7.95(1H, s)

Example 7

7) (R)-2-((2S,3S)-3-((R)-l-(tert-butyldimethylsilyloxy)ethyl)-4-oxoazinobutanone-2- Propionate

Add 14g of 30% hydrogen peroxide to the organic phase of Example 6, stir evenly, then add 3.5g of lithium hydroxide hydrate in batches at 8~15'C, add about 2h, high performance liquid phase detection Until the reaction is complete. The temperature was lowered to 0 to 5 t; 4N hydrochloric acid was added dropwise to the aqueous phase to pH = 2, and the organic phase was extracted. The aqueous phase was extracted once again with 10 ml of toluene, and the organic phases were combined. At 0~5 ° C, 6% sodium hydroxide solution was added dropwise, the pH was adjusted to between 9 and 10, and 17% Na ₂ S0 _{3 was added} until the KI starch test paper did not change blue. The mixture was allowed to stand for stratification, and the aqueous phase was collected; the organic phase was suction filtered, and the reaction flask, the separatory funnel and the filter residue were separately washed with a 1% NaOH solution, and the filtrate was layered to obtain an aqueous layer, and the aqueous layer was combined. The aqueous phase was transferred to a reaction flask, 60 ml of ethyl acetate was added, and the temperature was lowered to 0 to 5 ° C, stirred, and 4N hydrochloric acid brine was added dropwise to a pH of 2 to 3. Raise to 20'C, layer, collect the organic phase, vacuum to a semi-flow state, add 17g of petroleum ether, stir at -5~0'C for 1h under nitrogen, and filter 5.38g (yield: 97.4%) White crystal (R)-2-((2S,3S)-3-((R)-l-(tert-butyldimethylsilyloxy)ethyl)-4-oxoazepine-2 -Base) Propionic acid, dried below 40'C.

Mp 146~147°C,

[α] ²⁵ ο= +33.5° (c= 1.0, MeOH)

IR (KBr, cm ): 1740, 1465, 1330, 1255, 1043, 837.

1H-NMR (200 MHz, CDC 13): 0.08 (6H, s), 0.7 (9H, s), 1.24 (3H, d), 1.30 (3H, d, J = 7.5) _: 2.78 (1H, m), 3.06(1H, m), 3.98(1H, m), 4.24(1H, m), 6.37(1H).

Claims

Rights request

An intermediate for synthesizing a Pein drug, which has the structural formula shown by the following formula (I):

Wherein R ¹ represents a lower carbohydrocarbyl group, a nitro group, a halogen or a hydrogen element which is optionally substituted at a position; R ² is an aryl group, an alkyl group or an aryl fluorenyl group, and the aryl group, fluorenyl group or aryl group The base is also with or without a substituent.

The intermediate of a synthetic piranoid according to claim 1, wherein the aryl group is a phenyl group, a naphthyl group or a pyridyl group.

The intermediate of a synthetic piranoid according to claim 1, wherein the alkyl group is a low carbon radical of -C ₄ .

The intermediate of a synthetic piranoid according to claim 1, wherein the aryl fluorenyl group is a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group or a pyridylmethyl group.

The intermediate of a synthetic piranoid according to claim 1, wherein when the aryl group, the fluorenyl group or the aralkyl group has a substituent, the substituent is a single or a plurality of Halo, nitro, amino or cyano.

A method for producing an intermediate of a synthetic piranoid according to any one of claims 1 to 6, which comprises the steps of:

The compound of the formula (IV) and the compound of the formula (III) are dissolved in an organic solvent, and then reacted in the presence of an organic base to form a compound of the formula (V), the reaction temperature is -20 to 25' C, and the reaction time is 20 to 60 min _;

Dissolving the compound of the formula (V) and 2-bromopropionyl bromide in an organic solvent, and then reacting in the presence of an organic base to form a compound of the formula (I), that is, an intermediate of the synthetic piranoid, the reaction temperature is -20~ At 20 ° C, the reaction time is 0.51! ~ 24h;

The reaction route is as follows:

R ¹ represents a lower azeohydrocarbyl group, a nitro group, a halogen or a hydrogen element of an optionally substituted position of 〜; R ² is an aryl group, an alkyl group or an aryl fluorenyl group, or an aryl group, a fluorenyl group or an aryl fluorenyl group Without substituents;

Wherein the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, dimethylamine, pyridine, 2,6-lutidine or diphenylamine; the organic solvent is selected from the group consisting of dichloromethane, 1, 2 - one or more of dichloroacetamidine, tetrahydrofuran, dimethylformamide, dimethoxyacetamidine, diisopropyl ether, dimethyl sulfoxide and acetonitrile;

The equivalent ratio of each reactant is a compound of the formula (ΠΙ): the compound of the formula (IV) is 0.8 to 1.5, the organic base in the reaction of the first step: the compound of the formula (ΠΙ) is 1.0 to 1.5; 2-bromopropionyl bromide: The compound of the formula (V) 3⁄4 0.8-2.5, the organic base in the reaction of the second step: the compound of the formula (V) is 1.0 to 2.0;

The method according to claim 6, wherein the R ² is preferably a phenyl group, a tolyl group, a chlorophenyl group, a nitrophenyl group, a benzyl group or a methyl group.

The use of the intermediate of the synthetic piranoid according to claims 1 to 6, which is characterized in that it is used for the preparation of β-methylazetidin-2-one, that is, a compound of the following formula (Π), a specific method as follows:

a) reacting a compound of the formula (I) and the formula (VI) in a solvent under a zinc powder to obtain a compound of the formula (W); b) hydrolyzing the compound of the formula (II) under basic conditions to give a compound of the formula (II) while releasing the hands Sex reagent (V); The reaction route is as follows:

The equivalent ratio of each reactant is a compound of the formula (I): the compound of the formula (VI) is 0.8 to 2.0, the metal catalyst: the compound of the formula (VI) is 2.0 to 4.0, the solvent: the mass ratio of the compound of the formula (VI) is 6.0 to 10.0; The metal catalyst is zinc powder or magnesium powder;

The solvent is selected from one or more of dichloromethane, 1,2-dimethoxyacetamidine, tetrahydrofuran, diethyl ether, and toluene;

The alkaline condition is an aqueous solution of lithium hydroxide, sodium hydroxide or lithium hydroxide / hydrogen peroxide, and the amount of the base is equivalent to 2.0 to 4.0 equivalents of the compound of the formula (V;

The reaction temperature of the step a) is 0 to 30 ° C, and the reaction time is 1.5 to 4.0 h; the reaction temperature of the step b) is -10 to 25 ° C, and the reaction time is 4.0 to 8.0 h.

The use of an intermediate for synthesizing a piranoid according to claim 8, wherein the β-methylazetidin-2-one is further synthesized to prepare a carbapenem antibiotic.