CN113929684B - Meropenem intermediate and preparation method thereof - Google Patents
Meropenem intermediate and preparation method thereof Download PDFInfo
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- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/18—Oxygen atoms
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- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
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- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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Abstract
The application belongs to the technical field of medicines, and particularly relates to a meropenem intermediate and a preparation method thereof. The application provides a meropenem intermediate, which has a structure shown in a formula I; r is selected from C1-C6 alkyl, optionally substituted phenyl or optionally substituted benzyl. The preparation method of the meropenem intermediate comprises the following steps: mixing an azabicyclo compound, a chloroformate compound, a first organic base and an organic solvent for reaction to obtain a meropenem intermediate; the azabicyclo compound has a structure shown in a formula II, the chloroformate compound has a structure shown in a formula III, and the meropenem intermediate has a structure shown in a formula I. The application provides a meropenem intermediate and a preparation method thereof, which can effectively overcome the technical defects that a phosphorus-containing reagent cannot be recovered in the existing meropenem synthesis process, the water body and ecological environment are not friendly, the environment is polluted, and the solid-liquid waste liquid treatment cost is increased.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a meropenem intermediate and a preparation method thereof.
Background
Meropenem with the chemical name: (-) - (4R,5S,6S) -3- [ [ (3S,5S) -5- (dimethylcarbamoyl); preparing Meinuo into a south; 3- [ [5- [ (dimethylamino) carbonyl ] -3-pyrrolidinyl ] thio ] -6- (1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylic acid, is a carbapenem antibiotic, has the characteristics of wide antibacterial spectrum and strong antibacterial activity, and is used for treating various infections, including meningitis and pneumonia. Is one of the important medicaments for treating severe and multi-drug resistant bacteria infection at present, and is more and more widely applied in clinic. Therefore, the improvement of the traditional process of the medicine has good economic and social benefits.
In recent years, with the increase of environmental protection pressure and the wide acceptance of sustainable and stable development in the whole society, green chemistry has been receiving attention from governments, academic circles and enterprises of various countries. The use of green reagents and less waste treatment are important ways for realizing environmental friendliness. However, the existing meropenem synthesis process generates a byproduct diphenyl phosphate, which increases the purification steps of target products, and also needs to use a large amount of phosphorus-containing reagents, which are not recyclable, and thus, are not friendly to water and ecological environment, pollute the environment, and increase the cost for treating solid-liquid waste liquid.
Disclosure of Invention
In view of the above, the application provides a meropenem intermediate and a preparation method thereof, which can effectively solve the technical defects that a phosphorus-containing reagent cannot be recovered in the existing meropenem synthesis process, the phosphorus-containing reagent is not friendly to water and ecological environment, the environment is polluted, and the solid-liquid waste liquid treatment cost is increased.
The application provides a meropenem intermediate with a structure shown in a formula I;
in the formula I, R is selected from C1-C6 alkyl, optionally substituted phenyl or optionally substituted benzyl.
The second aspect of the application discloses a preparation method of the meropenem intermediate, which comprises the following steps:
mixing an azabicyclo compound, a chloroformate compound, a first organic base and an organic solvent for reaction to obtain a meropenem intermediate;
the azabicyclo compound has a structure shown in a formula II, the chloroformate compound has a structure shown in a formula III, and the meropenem intermediate has a structure shown in a formula I;
and R is selected from C1-C6 alkyl, optionally substituted phenyl or optionally substituted benzyl.
Specifically, the synthetic route of the meropenem intermediate is as follows:
specifically, R is selected from ethyl chloroformate or isopropyl chloroformate.
Specifically, R is selected from ethyl chloroformate.
In another embodiment, the first organic base is selected from one or more of triethylamine, N-diisopropylamine, pyridine, 2, 6-lutidine, and tetramethylguanidine;
the organic solvent is selected from one or more of dichloromethane, ethyl acetate, acetonitrile, butyl acetate, propyl acetate, tetrahydrofuran, acetone and N-methyl pyrrolidone.
Specifically, the first organic base is triethylamine.
Specifically, the organic solvent is dichloromethane or/and ethyl acetate.
In another embodiment, the reaction temperature of the meropenem intermediate is-40 ℃ to 0 ℃; the reaction time of the meropenem intermediate is 0.5-3 h.
Specifically, the reaction temperature of the meropenem intermediate is-25 ℃ to-20 ℃, and is further preferably-25 ℃ or-20 ℃; further preferably, the reaction time of the meropenem intermediate is 0.5-1 h.
The third aspect of the application provides a preparation method of meropenem, which comprises the following steps:
the azabicyclo compound has a structure shown in a formula II, the chloroformate compound has a structure shown in a formula III, and the meropenem intermediate has a structure shown in a formula I;
the meropenem side chain has a structure shown in formula IV; the undedeprotected meropenem has a structure shown in formula V; the meropenem has a structure shown in formula VI;
r is selected from C1-C6 alkyl, optionally substituted phenyl or optionally substituted benzyl;
In another embodiment, the molar ratio of the azabicyclo compound, the chloroformate compound, the first organic base, the meropenem side chain, and the second organic base is 1 (0.8-2): 0.5-1.5): 0.5-2.
In another embodiment, the first organic base is selected from one or more of triethylamine, N-diisopropylamine, pyridine, 2, 6-lutidine, and tetramethylguanidine;
the second organic base is selected from one or more of triethylamine, N-diisopropylamine, pyridine, 2, 6-dimethylpyridine and tetramethylguanidine;
the organic solvent is selected from one or more of dichloromethane, ethyl acetate, acetonitrile, butyl acetate, propyl acetate, tetrahydrofuran, acetone and N-methyl pyrrolidone.
Specifically, the first organic base is triethylamine.
Specifically, the second organic base is tetramethylguanidine.
Specifically, the organic solvent in step 1 is dichloromethane or/and ethyl acetate.
Specifically, the organic solvent in step 2 is acetonitrile.
In another embodiment, in step 1, the reaction temperature of the meropenem intermediate is-40 ℃ to 0 ℃; the reaction time of the meropenem intermediate is 0.5-3 h.
Specifically, in the step 1, the reaction temperature is-25 ℃ to-20 ℃, and more preferably-25 ℃ or-20 ℃; further preferably, the reaction time is 0.5-1 h.
In another embodiment, in the step 2, the reaction temperature is-30 ℃ to 0 ℃; the reaction time is 1-6 h.
Specifically, in the step 2, the reaction temperature is 15 ℃ to-10 ℃, and more preferably-15 ℃ or-10 ℃; in the step 2, the reaction time is further preferably 1-2 h.
In another embodiment, in the step 2, the concentration temperature is 30-60 ℃; the crystallization temperature is-10 ℃ to 10 ℃; the drying temperature is 30-60 ℃.
Specifically, in the step 2, the concentration temperature is more preferably 30-45 ℃, and further preferably 30 ℃ or 45 ℃; the crystallization temperature is more preferably 0-5 ℃, and further preferably 0 ℃ or 5 ℃; the drying temperature is more preferably 30 ℃ to 35 ℃, and further preferably 30 ℃ or 35 ℃.
Specifically, the washing is performed by using brine; the crystallization comprises cooling crystallization in an ethyl acetate environment.
Specifically, the drying is vacuum drying.
In another embodiment, the catalyst is selected from one or more of palladium on carbon, raney nickel, and zinc powder.
Specifically, the synthetic route of meropenem is as follows:
the method adopts chloroformate compounds (formula III) to replace the traditional diphenyl chlorophosphate to activate azabicyclo compounds (formula II) to obtain meropenem intermediates (formula I), namely enol carboxylate compounds of bicyclic parent nucleus, and the reaction time of the step is shortened to 0.5h compared with the traditional reaction time. The meropenem intermediate is continuously condensed with a meropenem side chain (formula IV), the reaction time of the step is shortened to 1h compared with the traditional reaction time, main byproducts are replaced ethanol and isopropanol, the two byproducts do not need to be removed, the traditional method adopts diphenyl chlorophosphate as an activating reagent, after the condensation reaction, the removal of the diphenyl chlorophosphate needs to be considered, the steps of washing, purification and the like are increased, the treatment cost of solid waste liquid is increased, and the method is not environment-friendly. The meropenem synthesis process is simple, compact, controllable, green and environment-friendly, mild in production conditions, short in reaction time, beneficial to industrial production, high in production efficiency and great in economic potential.
Compared with the prior art, the beneficial effects of the application at least comprise the following aspects:
the meropenem intermediate (shown in formula I) prepared by the method is high in yield and purity.
The method has the advantages that in the process of synthesizing the meropenem by adopting the meropenem intermediate (shown in formula I), the byproducts are ethanol and isopropanol, reaction byproducts are removed without washing and purifying, the operation is simple, the preparation time is short, the method is suitable for industrial application, and the method has great economic potential.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
Fig. 1 is a mass spectrum of a meropenem intermediate represented by formula I provided in example 1 of the present application;
fig. 2 is a mass spectrum of the meropenem intermediate shown in formula I provided in example 3 of the present application;
FIG. 3 is an HPLC plot of deprotected meropenem of formula V provided in example 4 of the present application;
FIG. 4 is an HPLC plot of deprotected meropenem of formula V provided in example 2 of the present application;
FIG. 5 is an HPLC plot of deprotected meropenem of formula V provided in example 6 of the present application;
fig. 6 is an HPLC plot of the deprotected meropenem of formula V provided in comparative example 4 of the present application.
Detailed Description
The application provides a meropenem intermediate and a preparation method thereof, and a preparation method of meropenem, and is used for solving the technical defects that a phosphorus-containing reagent cannot be recovered in the existing meropenem synthesis process, the water body and ecological environment are not friendly, the environment is polluted, and the solid-liquid waste liquid treatment cost is increased.
The technical solutions in the embodiments of the present application will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
The raw materials and reagents used in the following examples are commercially available or self-made.
The azabicyclo compounds of formula II in the following examples can be prepared by any method known in the art, such as CN1824666A or USP 4933333.
Example 1
The embodiment of the application provides a meropenem intermediate shown as a formula I, and the specific preparation method comprises the following steps:
according to the following synthetic route, 50ml of dichloromethane, 10g of azabicyclo compound shown in formula II and 3.3g of ethyl chloroformate (1.1 eq) are added into a four-mouth flask, and the temperature is reduced to-25 ℃; 3.35g of triethylamine (1.2 eq) is added dropwise and reacted for 0.5h at-25 ℃, and the product is ready for use and is the meropenem intermediate shown in the formula I. Mass spectral data of the reaction solution, MS (M + 1: 435.13).
The meropenem intermediate shown in formula I is named as (4R, 5R, 6S) -3- (ethoxycarboxyl) -6- ((R) -1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid- (4-nitro) benzyl ester.
The mass spectrum of the meropenem intermediate shown in formula I of the examples of the present application was measured, and the results are shown in FIG. 1, wherein the number 1 is m/z:102.1, the number 2 is m/z:196.1, the number 3 is m/z:277.1, the number 4 is m/z:349.1, the number 5 is m/z:350.0, the number 6 is m/z:435.1, the number 7 is m/z:436.1, the number 8 is m/z:869.3, the number 9 is m/z:871.3, and the number 10 is m/z:886.4 in FIG. 1.
Example 2
The embodiment of the application provides an unprotected meropenem shown as a formula V, and the specific preparation method comprises the following steps:
according to the following synthetic route, 50ml of acetonitrile and 9.75g of meropenem side chain (1.0 eq) shown in formula IV are added into the product of the example 1, and the temperature is reduced to-15 ℃; 3.82g of tetramethylguanidine (1.2 eq) was added dropwise and reacted at-15 ℃ for 1 hour. After the reaction, 50ml of saturated brine was added, and the mixture was washed, separated, and the aqueous phase was extracted three times with 150ml of ethyl acetate, and the organic phases were combined. Concentrating the organic phase at 45 deg.C to obtain oily substance, adding 50ml ethyl acetate, stirring, dissolving, cooling to 0 deg.C, stirring, crystallizing for 2 hr, filtering, and oven drying at 35 deg.C to obtain 17.66g of undedeprotected meropenem represented by formula V, with two-step molar yield of 92% and HPLC detection purity of 98.942%.
The deprotected meropenem represented by formula V is named as (4R,5S,6S) -3- [ [ (3S,5S) -5- [ (dimethylamino) formyl-1- [ [ (4-nitrobenzyl) oxy ] carbonyl ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester.
Example 3
The embodiment of the application provides a meropenem intermediate shown as a formula I, and the specific preparation method comprises the following steps:
according to the following synthetic route, 50ml of dichloromethane, 10g of azabicyclo compound shown in formula II and 3.74g of isopropyl chloride (1.1 eq) are added into a four-mouth flask, and the temperature is reduced to-20 ℃; 3.35g of triethylamine (1.2 eq) is added dropwise and reacted for 0.5h at-20 ℃, and the product is ready for use and is the meropenem intermediate shown in the formula I. Mass spectral data of the reaction solution, MS (M + 1: 449.15).
The meropenem intermediate shown as the formula I is (4R, 5R, 6S) -3- (isopropyloxycarbonyl) -6- ((R) -1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid- (4-nitro) benzyl ester.
The mass spectrum of the meropenem intermediate shown in formula I of the example of the application is detected, and the result is shown in figure 2.
Example 4
The embodiment of the application provides an unprotected meropenem shown as a formula V, and the specific preparation method comprises the following steps:
according to the following synthetic route, 50ml of acetonitrile and 9.75g of meropenem side chain (1.0 eq) shown in formula IV are added into the product of the example 3, and the temperature is reduced to-10 ℃; 3.82g of tetramethylguanidine (1.2 eq) was added dropwise and reacted at-10 ℃ for 1 hour. After the reaction, 50ml of saturated brine was added, and the mixture was washed, separated, and the aqueous phase was extracted three times with 150ml of ethyl acetate, and the organic phases were combined. Concentrating the organic phase at 30 deg.C to obtain oily substance, adding 50ml ethyl acetate, stirring, dissolving, cooling to 5 deg.C, stirring, crystallizing for 2 hr, filtering, and oven drying at 30 deg.C to obtain 17.86g of undedeprotected meropenem represented by formula V, with two-step molar yield of 93% and purity of 99.339% by HPLC.
The deprotected meropenem represented by formula V is named as (4R,5S,6S) -3- [ [ (3S,5S) -5- [ (dimethylamino) formyl-1- [ [ (4-nitrobenzyl) oxy ] carbonyl ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester.
Example 5
The embodiment of the application provides a meropenem intermediate shown as a formula I, and the specific preparation method comprises the following steps:
adding 150ml of dichloromethane, 30g of azabicyclo compound shown in formula II and 10.2g of isopropyl chloride (1.0 eq) into a four-neck flask, and cooling to-20 ℃; 10g of triethylamine (1.2 eq) is added dropwise and reacted for 0.5h at-25 ℃, and the product is ready for use and is a meropenem intermediate shown in formula I.
The meropenem intermediate shown in formula I is named as (4R, 5R, 6S) -3- (isopropyloxycarboxyl) -6- ((R) -1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid- (4-nitro) benzyl ester.
Example 6
The embodiment of the application provides an unprotected meropenem shown as a formula V, and the specific preparation method comprises the following steps:
150ml of acetonitrile and 29.3g (1.0 eq) of meropenem side chain represented by formula IV were added to the product of example 5, and the temperature was reduced to-10 ℃; 12.5g of triethylamine (1.1 eq) was added dropwise and the reaction was carried out at-15 ℃ for 1 hour. After the reaction, 150ml of saturated brine was added, and the mixture was washed, separated, and the aqueous phase was extracted three times with 450ml of ethyl acetate, and the organic phases were combined. Concentrating the organic phase at 45 deg.C to obtain oily substance, adding 150ml ethyl acetate, stirring, dissolving, cooling to 0 deg.C, stirring, crystallizing for 2 hr, filtering, and oven drying at 35 deg.C to obtain 52.4g of undedeprotected meropenem represented by formula V, with two-step molar yield of 91% and purity of 98.328% by HPLC.
The deprotected meropenem represented by formula V is named as (4R,5S,6S) -3- [ [ (3S,5S) -5- [ (dimethylamino) formyl-1- [ [ (4-nitrobenzyl) oxy ] carbonyl ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester.
Example 7
The embodiment of the application provides a meropenem intermediate shown as a formula I, and the specific preparation method comprises the following steps:
adding 50ml of dichloromethane, 10g of azabicyclo compound shown in formula II and 3.74g of isopropyl chloride (1.1 eq) into a four-neck flask, and cooling to-20 ℃; 3.81g of tetramethylguanidine (1.2 eq) is added dropwise and reacted for 0.5h at-20 ℃, and the product is reserved and is a meropenem intermediate shown in the formula I.
The name of the meropenem intermediate shown in the formula I is as follows: (4R, 5R, 6S) -3- (isopropyloxycarboxylyl) -6- ((R) -1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid- (4-nitro) benzyl ester.
Example 8
The embodiment of the application provides an unprotected meropenem shown as a formula V, and the specific preparation method comprises the following steps:
adding 50ml of acetonitrile and 9.75g of meropenem side chain (1.0 eq) shown in formula V into the product of the example 7, and cooling to-15 ℃; 3.82g of tetramethylguanidine (1.2 eq) was added dropwise and reacted at-15 ℃ for 1 hour. The reaction solution is monitored by HPLC, and the deprotected meropenem shown in the formula V accounts for a small amount, so that the reaction effect is poor.
The deprotected meropenem represented by formula V is named as (4R,5S,6S) -3- [ [ (3S,5S) -5- [ (dimethylamino) formyl-1- [ [ (4-nitrobenzyl) oxy ] carbonyl ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester.
Comparative example 1
The application provides a meropenem intermediate shown in a formula I and prepared by taking N, N-diisopropylethylamine as an organic base, and the specific preparation method comprises the following steps:
adding 50ml of dichloromethane, 10g of azabicyclo compound shown in formula II and 3.74g of isopropyl chloride (1.1 eq) into a four-neck flask, and cooling to-25 ℃; 4.28g of N, N-diisopropylethylamine (1.2 eq) is added dropwise, and the product is ready for use and is a meropenem intermediate shown in the formula I. With the dropwise addition, an oily substance begins to appear in the system, a small amount of the oily substance is taken for spectrum analysis, and a large amount of raw materials (the azabicyclo compound shown in the formula II) also remain. Therefore, the reaction effect is poor when N, N-diisopropylethylamine is used as an organic base catalyst.
The meropenem intermediate name shown in formula I: (4R, 5R, 6S) -3- (isopropyloxycarboxylyl) -6- ((R) -1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid- (4-nitro) benzyl ester.
Comparative example 2
The application provides a meropenem intermediate shown in a formula I and prepared by taking N, N-diisopropylethylamine as an organic base, and the specific preparation method comprises the following steps:
adding 50ml of dichloromethane, 10g of azabicyclo compound shown in formula II and 3.3g of ethyl chloroformate (1.1 eq) into a four-neck flask, and cooling to-25 ℃; 4.28g of N, N-diisopropylethylamine (1.2 eq) is added dropwise, and the product is ready for use and is a meropenem intermediate shown in the formula I. After the dropwise addition, the reaction is continued, an oily substance is slowly separated out, a small amount of the oily substance is taken for spectrum analysis, and a large amount of raw materials (the azabicyclo compound shown in the formula II) are remained. Therefore, the adjustment of the amount of the reaction system and the use of N, N-diisopropylethylamine as the organic base catalyst result in poor reaction effect and oily reaction of the system.
The meropenem intermediate shown in formula I is named as (4R,5S,6S) -3- [ [ (3S,5S) -5- [ (dimethylamino) formyl-1- [ [ (4-nitrobenzyl) oxy ] carbonyl ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester.
Comparative example 3
The application provides a method for synthesizing a meropenem intermediate by adopting the conventional synthetic route, and the specific method comprises the following steps:
the conventional synthetic route for synthesizing meropenem is as follows, the conventional meropenem generally takes a compound 1 as a mother nucleus, an enol phosphate product (a compound 2) of a bicyclic mother nucleus can be obtained by activating diphenyl chlorophosphate, then the enol phosphate product is condensed with a meropenem side chain to obtain protected non-deprotected meropenem, and the non-deprotected meropenem is subjected to hydrogenation reduction under the condition of a catalyst to obtain the meropenem.
According to the following synthetic route, 150ml of dichloromethane, 30g of azabicyclo compound shown in formula II and 22.6g of diphenyl chlorophosphate (1.1 eq) are added into a four-mouth flask, and the temperature is reduced to-25 ℃; 10g of triethylamine (1.2 eq) is added dropwise and reacted for 5h at-25 ℃ to obtain a product for later use, thus obtaining the compound 2.
Comparative example 4
The application provides a method for synthesizing the deprotected meropenem shown in the formula V by adopting the conventional synthetic route, and the specific preparation method comprises the following steps:
adding 150ml of acetonitrile and 29.3g of meropenem side chain shown in formula IV into the product liquid of the comparative example 3, and cooling to-10 ℃; 14.1g of N, N-diisopropylethylamine (1.1 eq) was added dropwise and the reaction was carried out at-10 ℃ for 6 hours. After the reaction, 600ml of 6% sodium dihydrogen phosphate is added for washing four times, the diphenyl phosphate is detected to be less than 1.5% by an organic phase, the layers are separated, the combined water phase is extracted with 450ml ethyl acetate for three times, and the organic phase is combined. Concentrating the organic phase at 45 ℃ to obtain an oily substance, adding 150ml of ethyl acetate, stirring, dissolving, cooling to 0 ℃, stirring, crystallizing for 2 hours, filtering, and drying at 35 ℃ to obtain 48.38g of deprotected meropenem shown in formula V, wherein the two-step molar yield is 84%, and the purity is 97.813% by HPLC detection.
The name of the deprotected meropenem represented by the formula V is (4R,5S,6S) -3- [ [ (3S,5S) -5- [ (dimethylamino) formyl-1- [ [ (4-nitrobenzyl) oxy ] carbonyl ] -3-pyrrolidinyl ] thio ] -6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester.
TABLE 1 comparison of the Process Effect of chloroformate reagents and diphenylphosphoryl chloride
The reagents used in the left and right columns of Table 1 were ethyl chloroformate, isopropyl chloroformate or diphenyl chlorophosphate.
In conclusion, the obtained non-deprotected meropenem shown in formula V has high purity and yield, less waste water and short reaction time by using chloroformate reagents as activating reagents, and the used reagents are greatly reduced, so that the cost can be saved. The process is simple, compact, controllable, green and environment-friendly, has mild production conditions and short reaction time, is beneficial to industrial production, improves the production efficiency, and has great economic potential.
The foregoing is only a preferred embodiment of the present application and it should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present application, and these improvements and modifications should also be considered as the protection scope of the present application.
Claims (5)
1. A preparation method of meropenem is characterized by comprising the following steps:
step 1, mixing an azabicyclo compound, a chloroformate compound, a first organic base and an organic solvent for reaction to obtain a meropenem intermediate; the first organic base is triethylamine; the organic solvent in the step 1 is dichloromethane or/and ethyl acetate;
the azabicyclo compound has a structure shown in a formula II, the chloroformate compound has a structure shown in a formula III, and the meropenem intermediate has a structure shown in a formula I;
step 2, mixing the meropenem intermediate, the meropenem side chain, a second organic base and an organic solvent for reaction, and then sequentially washing, concentrating, crystallizing, filtering and drying a product to obtain the undeprotection meropenem; the second organic base is tetramethylguanidine; the organic solvent in the step 2 is acetonitrile;
step 3, carrying out reduction reaction on the meropenem which is not deprotected under the action of a catalyst to obtain meropenem;
the meropenem side chain has a structure shown in formula IV; the undedeprotected meropenem has a structure shown in formula V; the meropenem has a structure shown in formula VI;
r is selected from C1-C6 alkyl, optionally substituted phenyl or optionally substituted benzyl;
2. The method according to claim 1, wherein the molar ratio of the azabicyclo compound, the chloroformate compound, the first organic base, the meropenem side chain, and the second organic base is 1 (0.8-2): 0.5-1.5): 0.5-2.
3. The method according to claim 1, wherein the reaction temperature is-40 ℃ to 0 ℃ in step 1; the reaction time is 0.5-3 h.
4. The method according to claim 1, wherein the reaction temperature in step 2 is-30 ℃ to 0 ℃; the reaction time is 1-6 h; the concentration temperature is 30-60 ℃; the crystallization temperature is-10 ℃ to 10 ℃; the drying temperature is 30-60 ℃.
5. The method of claim 1, wherein the catalyst is selected from one or more of palladium on carbon, Raney nickel, and zinc powder.
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