CN111960984B - Preparation method of synthetic doripenem side chain intermediate - Google Patents

Preparation method of synthetic doripenem side chain intermediate Download PDF

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CN111960984B
CN111960984B CN202010951571.9A CN202010951571A CN111960984B CN 111960984 B CN111960984 B CN 111960984B CN 202010951571 A CN202010951571 A CN 202010951571A CN 111960984 B CN111960984 B CN 111960984B
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doripenem
side chain
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CN111960984A (en
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罗红梅
古志国
张祥明
熊云
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Jiangxi Ruyu Technology Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a preparation method of a synthetic doripenem side chain intermediate, which comprises the steps of taking a compound IV as a starting material, dissolving the compound IV in an organic solvent I, and introducing ammonia gas in the presence of a protective medium to obtain a compound V; wherein R is a protecting group on pyrrolidine N. The preparation method of the invention simplifies the synthesis steps, greatly shortens the production period, has no hazardous waste solid in the preparation process, and has high product yield, low cost and easily controlled quality.

Description

Preparation method of synthetic doripenem side chain intermediate
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method for synthesizing a doripenem side chain intermediate.
Background
The structural formula of the doripenem side chain is as follows:
Figure SMS_1
r is a protecting group on pyrrolidine N.
Doripenem side chain is a key intermediate necessary for doripenem, which is a novel broad-spectrum antibiotic of carbapenem developed by the company shonoogi in japan, and is marketed in japan for the first time in 2005, and doripenem can be used for treating urinary tract infections, respiratory tract infections, complicated intra-abdominal infections, and kidney and brain infections, and has a high inhibitory activity on gram-positive bacteria as Yu Meiluo penem, and a higher inhibitory activity on gram-negative bacteria than imipenem.
According to literature reports, the doripenem side chain synthesis routes in the prior art are roughly two of the following:
1. route one: japanese Shionogi company (Organic Process Research & development, 2003, volume 7, pages 649-654) reports the synthetic route as follows:
Figure SMS_2
2. route two: the synthetic route reported in european patent document EP0528678A1 is as follows:
Figure SMS_3
both routes are to reduce the ester to the alcohol and then to obtain the target product via a multi-step reaction.
In the first route, the cost of side chain raw materials for synthesizing doripenem is high, the energy consumption is high, for example, in the process of preparing the compound 6 from the compound 5, 24.3Kg of the compound 5 needs to consume 21.9Kg of triphenylphosphine and 16.7Kg of azodiisopropyl ester (Organic Process Research & development pmnt,2003, volume 7, page 653), the usage amount of triphenylphosphine and azodiisopropyl ester is large, a large amount of dangerous solid waste is generated after the reaction is finished, and byproducts generated by the triphenylphosphine and azodiisopropyl ester in the reaction process are difficult to remove.
In the second route, the reaction steps are more, the used reagents are more, and the cost of the obtained doripenem side chain is higher.
In summary, the two processes for preparing the side chains are complex, and the quality risk and the cost are high for subsequent products, so that the preparation process has long period, low yield and high raw material cost.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method for synthesizing a doripenem side chain intermediate, which has the advantages of short production period, no dangerous solid waste in the preparation process, high product yield, low cost and easy quality control.
A method of preparing a synthetic doripenem side chain intermediate comprising: dissolving a compound IV serving as a starting material in an organic solvent I, and introducing ammonia gas in the presence of a protective medium to obtain a compound V; the specific reaction process is as follows:
Figure SMS_4
wherein R is a protecting group on pyrrolidine N, preferably t-butoxycarbonyl, p-nitrobenzoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, allyloxycarbonyl or diisopropylphosphono.
The preparation method comprises the following steps:
the organic solvent I is preferably an alcohol solvent or a mixed solvent containing alcohol, wherein the mixed solvent comprises an alcohol solvent with better ammonia solubility and a solvent B with better solubility for the compound IV; the alcohol solvent is one or more of methanol, ethanol, isopropanol and n-butanol; the solvent B is one or more of dichloromethane, chloroform, benzene and toluene; the volume ratio of the alcohol solvent to the solvent B in the mixed solvent is (2-10): 1. As a further preferred option, the alcohol solvent is isopropanol, which not only ensures higher solubility to ammonia gas, but also has certain solubility to the compound IV. Further preferably, in the mixed solvent, the volume ratio of the alcohol solvent to the solvent B is (5 to 10): 1.
The protective medium has the function of avoiding the generated mercapto group from generating disulfide through oxidative coupling; preferably, the protecting medium is tri-n-butyl phosphine or inert gas, and the protecting medium is further preferably tri-n-butyl phosphine because ammonia gas is required to be introduced later for control; when tri-n-butylphosphine is selected as the protective medium, the weight ratio of tri-n-butylphosphine to the compound IV is 1 (20-60), and more preferably 1: (30-40), relatively, the addition amount of tri-n-butyl phosphine is small, the post-treatment difficulty is reduced, and the three-waste problem is avoided.
Preferably, the reaction temperature for preparing the compound V from the compound IV is-10-40 ℃, and further preferably, ammonia gas is introduced, and the reaction temperature is preferably-5 ℃, so that the occurrence of side reactions is further reduced. Preferably, the weight ratio of ammonia gas to the compound IV is 1 (6-20); further preferably 1: (10-20). Preferably, after the incubation reaction in this step is completed, hydrochloric acid with a concentration of 1-30% is used to adjust the pH to 3-4. Preferably, the reaction time of ammonia gas with compound IV is 3 to 25 hours, more preferably 3 to 5 hours.
As a specific preferred mode, the preparation method of the side chain intermediate of the synthetic doripenem comprises the steps of dissolving a compound IV in an organic solvent I, dissolving, cooling in the presence of a protective medium, introducing ammonia gas, and carrying out heat preservation reaction for 3-25 h; adjusting the pH to be 3-5 with hydrochloric acid, filtering, concentrating the filtrate to be dry, adding an organic solvent II for dissolving, washing with saturated saline, concentrating and crystallizing the organic phase to obtain a compound V. Preferably, the organic solvent II is one or more of ethyl acetate, butyl acetate, methylene dichloride and toluene.
Preferably, the preparation method of the compound IV comprises the following steps: carrying out hydroxymethyl esterification reaction on the compound II and methylsulfonyl chloride in the presence of an acid binding agent to obtain a compound III; the compound III reacts with KSAc at 30-80 ℃ to obtain the compound IV, and the specific reaction process is as follows:
Figure SMS_5
preferably, the molar ratio of the compound II to the acid binding agent and the methylsulfonyl chloride is 1: (1-5): (1-5); further preferably 1: (1-2): (1-2).
Further preferably, the molar ratio of the compound III to KSAc is 1 (1-5), and further preferably 1 (1-2).
As a further preference, the reaction time for the preparation of compound IV from compound III is from 5 to 20 hours.
Further preferably, the preparation method of the compound IV comprises the following steps:
dissolving a compound II in dichloromethane (chloroform, toluene and other solvents can be adopted), cooling to below-5 ℃, then adding triethylamine, stirring, dropwise adding methylsulfonyl chloride for carrying out hydroxymethyl esterification, adding water for quenching reaction after the reaction is finished, layering, concentrating an organic layer, and adding ethyl acetate into a concentrate for crystallization to obtain a compound III;
dissolving a compound III in DMF (or adopting solvents such as DMSO) and the like, adding KSAc, heating to 30-80 ℃, carrying out heat preservation reaction for 5-20 hours, slowly pouring the reaction solution into ice water at 0-10 ℃ after heat preservation is finished, precipitating solid, filtering, washing with water and drying to obtain the compound IV.
Preferably, the preparation method of the synthetic doripenem side chain intermediate of the present application further comprises: the compound V undergoes a reduction reaction under the action of a carbonyl reducer to obtain a compound VI; under the protection of nitrogen and in the presence of an acid binding agent, the compound VI reacts with trimethylchlorosilane and sulfamoyl chloride at the temperature of-80 to-40 ℃ to obtain a compound I; the specific reaction process is as follows:
Figure SMS_6
in the preparation method, in the process of preparing the compound VI from the compound V:
preferably, the reaction solvent is one or more of tetrahydrofuran, methyl tetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, isopropyl ether and dioxane. Preferably, the carbonyl reducing agent is one or more of borane, diborane, sodium borohydride, potassium borohydride, and lithium borohydride. Preferably, the reaction temperature is 60-80 ℃, the reaction time is 0.5-24 h, and the mass ratio of the carbonyl reducer to the substances of the compound V is (0.5-8): 1; further preferably (1-2): 1; more preferably (1 to 1.5): 1.
In the preparation method, in the process of preparing the compound I from the compound VI: the reaction solvent is one or more of dichloromethane, chloroform, dioxane and toluene. The molar ratio of the compound VI to the trimethylchlorosilane, the sulfamoyl chloride and the acid binding agent is 1: (1-2): (1-2): (1-5). The reaction temperature is-80 to-40 ℃.
In the present invention, the acid-binding agent may be an organic base such as triethylamine or an inorganic base such as sodium carbonate. The molar ratio of the acid-binding agent to the corresponding substrate is preferably (1-2): 1.
Further preferred is a process for preparing compound i from compound v:
dissolving a compound V in a reaction solvent, adding a carbonyl reducer under the protection of nitrogen to reduce amide into ammonia, adding methanol to quench the reaction, regulating pH to 3-4 with dilute hydrochloric acid, layering, concentrating an organic layer to dryness, adding ethyl acetate to crystallize and dry to obtain a compound VI;
dissolving a compound VI in dichloromethane, cooling to-80 to-40 ℃ under the protection of nitrogen, adding triethylamine, dropwise adding trimethylchlorosilane, and stirring after dropwise adding; adding triethylamine, dropwise adding dichloromethane solution of sulfamoyl chloride, and stirring after the dropwise adding is finished; adding dilute hydrochloric acid and methanol mixed solution, stirring, washing with brine to obtain an organic phase, concentrating the organic phase until the organic phase is dry, and adding ethyl acetate for crystallization to obtain the compound I.
The invention can prepare the compound I from the compound II, and the reaction process is as follows:
Figure SMS_7
/>
of course, the compound V can also be prepared directly from a commercially available compound III or compound IV, so as to obtain a compound VI, and finally, the compound I is obtained.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention simplifies the synthesis steps, directly converts the compound IV into the compound V by utilizing ammonia gas, avoids the reduction step of ester groups, and further avoids the use of triphenylphosphine and azodiisopropyl ester which are difficult to treat and have high solid waste.
2. The invention has short reaction period, and compared with the existing route II, the invention reduces the reaction period to four reaction steps, thereby greatly shortening the production period.
3. The invention has good reaction selectivity, high product purity and high yield.
4. The invention has mild reaction condition and does not need high-risk reaction.
5. The preparation method has the advantages that the separation operation of the product and the intermediate is simple, the intermediate in the doripenem route is synthesized without being refined, and the product can directly participate in the synthesis of the required compound; the final product can not have harsh conditions when being used for subsequent reaction, and can ensure the cost and quality control of the subsequent product.
In short, the invention adopts ammonia gas as raw material, and leads the ammonia gas to simultaneously react with the thioacetyl group and the ester group in the compound IV to generate sulfhydryl group and amide group, thus generating the compound V, and simultaneously introducing NH 2 The functional group omits the subsequent amination reaction, simplifies the synthesis steps and shortens the reaction period; triphenylphosphine and azodiisopropyl ester in the traditional process are avoided in the reaction process, and dangerous solid waste is avoided.
Detailed Description
Example 1
A preparation method for synthesizing doripenem side chain intermediate comprises the following reaction processes:
Figure SMS_8
/>
the method comprises the following specific steps: dissolving a compound II (10.00 g,0.0308 mol) in dichloromethane (100 ml), cooling to below-5 ℃, then adding triethylamine (4.67 g,0.0462 mol) and stirring for 5 minutes, dropwise adding methylsulfonyl chloride (4.24 g,0.0370 mol) for hydroxymethyl esterification, adding water after the reaction is finished for quenching reaction, layering, concentrating an organic layer, adding ethyl acetate (50 ml) into a concentrate for crystallization to obtain a compound III (10.91 g, purity 98% and molar yield 88%);
dissolving a compound III (10.00 g,0.0249 mol) in DMF (80 ml), adding KSAc (4.27 g,0.0374 mol) after dissolving, heating to 50 ℃, keeping the temperature for reaction for 10 hours, slowly pouring the reaction solution into ice water at 0 ℃ after the heat preservation is finished, separating out a solid, filtering, washing and drying to obtain a compound IV (8.57 g, purity 98% and molar yield 90%);
compound iv (8.00 g,0.0209 mol) was dissolved in a mixed solvent of isopropanol (55 ml) and dichloromethane (11 ml), tri-n-butylphosphine (0.27 g,0.0013 mol) was added to the solution, the temperature was reduced to-5 ℃, ammonia gas (0.8 g,0.0470 mol) was slowly introduced, and the reaction was carried out for 3 hours under heat preservation; adjusting pH to 4 with 5% hydrochloric acid, filtering, concentrating the filtrate to dryness, adding ethyl acetate (150 ml) to dissolve, washing with saturated brine, concentrating and crystallizing the organic phase to obtain compound V (6.12 g, purity 98%, molar yield 90%);
the nuclear magnetic data for compound v are as follows:
1 H-NMRδ(DMSO)ppm:1.3(m,1H),2.17-2.42(m,2H),2.85(m,1H) 3.58-3.83(m,2H),4.39(m,1H),5.02(s,2H),7.21(s,2H)7.58(d,J＝9Hz,2H),8.14(d,J＝9Hz,2H)；
compound V (5.50 g,0.0169 mol) was dissolved in THF (50 ml) and borane (0.35 g,0.0254 mol) was added under nitrogen protection at 70℃for 10h; after the reaction, 5ml of methanol was added, the pH=4 was adjusted with hydrochloric acid, the mixture was kept for 3 hours, the layers were separated, the organic layer was concentrated to dryness, and ethyl acetate (20 ml) was added for crystallization to give Compound VI (3.95 g, purity 97%, molar yield 75%);
the nuclear magnetic data of compound vi are as follows:
1 H-NMRδ(CDCl3)ppm:1.63-1.90(m,1H),2.48-2.68(m,1H),2.86-3.43(m, 4H),3.65-4.23(m,2H),5.22(s,2H),7.52(d,J＝9Hz,2H),8.23(d,J＝9Hz,2H)；
compound vi (3.00 g,0.0096 mol) was dissolved in dichloromethane, cooled to-75 ℃ under nitrogen protection, triethylamine (1.30 g,0.0128 mol) was added, trimethylchlorosilane (1.25 g, 0.0115 mol) was added dropwise, and stirring was performed for 2 hours; triethylamine (1.46 g,0.0144 mol) was added dropwise to a dichloromethane solution of sulfamoyl chloride (1.34 g,0.0116 mol), and the mixture was stirred for 1 hour; adding dilute hydrochloric acid and methanol mixed solution, stirring for 40 minutes, washing with brine to obtain an organic phase, concentrating the organic phase to dryness, adding ethyl acetate (20 ml) for crystallization to obtain a compound I (3.37 g, purity 98%, molar yield 75%);
the nuclear magnetic data of compound I are consistent with those of the prior document (EP 0528678A 1).
Example 2
A preparation method for synthesizing doripenem side chain intermediate comprises the following reaction processes:
Figure SMS_9
the method comprises the following specific steps: the preparation process of the compound IV is the same as that of the compound IV in the example 1;
compound iv (8.00 g,0.0209 mol) was dissolved in a mixed solvent of isopropanol (66 ml) and dichloromethane (8 ml), tri-n-butylphosphine (0.23 g,0.0011 mol) was added to the solution, the temperature was lowered to 0 ℃, ammonia gas (0.5333 g,0.0313 mol) was slowly introduced, and the reaction was carried out for 4 hours under heat preservation; adjusting pH to=3 with 10% hydrochloric acid, filtering, concentrating the filtrate to dryness, adding ethyl acetate (150 ml) to dissolve, washing with saturated brine, concentrating and crystallizing the organic phase to obtain compound V (6.05 g, purity 98%, molar yield 89%);
compound V (5.50 g,0.0169 mol) was dissolved in THF (50 ml), and borane (0.30 g,0.0220 mol) was added under nitrogen protection at 60℃for 20h; after the reaction, 5ml of methanol was added, the pH=4 was adjusted with hydrochloric acid, the mixture was kept for 3 hours, the layers were separated, the organic layer was concentrated to dryness, and ethyl acetate (20 ml) was added for crystallization to give Compound VI (4.00 g, purity 97%, molar yield 76%);
compound vi (3.00 g,0.0096 mol) was dissolved in dichloromethane, cooled to-60 ℃ under nitrogen protection, triethylamine (1.30 g,0.0128 mol) was added, trimethylchlorosilane (1.25 g, 0.0115 mol) was added dropwise, and stirring was performed for 2 hours; triethylamine (1.46 g,0.0144 mol) was added dropwise to a dichloromethane solution of sulfamoyl chloride (1.34 g,0.0116 mol), and the mixture was stirred for 1 hour; dilute hydrochloric acid and methanol mixture was added, stirred for 40 minutes, washed with brine to obtain an organic phase, concentrated to dryness, and added with ethyl acetate (20 ml) for crystallization to obtain compound i (2.74 g, purity 98%, molar yield 73%).
Example 3
A preparation method for synthesizing doripenem side chain intermediate comprises the following reaction processes:
Figure SMS_10
the method comprises the following specific steps: the preparation process of the compound IV is the same as that of the compound IV in the example 1;
compound iv (8.00 g,0.0209 mol) was dissolved in a mixed solvent of isopropanol (70 ml) and dichloromethane (7 ml), tri-n-butylphosphine (0.20 g,0.0010 mol) was added to the solution, the temperature was lowered to 5 ℃, ammonia gas (0.40 g,0.0235 mol) was slowly introduced, and the reaction was carried out for 5 hours under heat preservation; adjusting pH to 3 with 20% hydrochloric acid, filtering, concentrating the filtrate to dryness, adding ethyl acetate (150 ml) to dissolve, washing with saturated brine, concentrating and crystallizing the organic phase to obtain compound V (6.19 g, purity 98%, molar yield 91%);
compound V (5.50 g,0.0169 mol) was dissolved in THF (50 ml) and borane (0.28 g,0.0203 mol) was added under nitrogen protection at 80℃for 8h; after the reaction, 5ml of methanol was added, the pH=4 was adjusted with hydrochloric acid, the mixture was kept warm for 3 hours, the layers were separated, the organic layer was concentrated to dryness, ethyl acetate (20 ml) was added for crystallization and drying to obtain compound VI (3.84 g, purity 97%, molar yield 73%);
compound vi (3.00 g,0.0096 mol) was dissolved in dichloromethane, cooled to-45 ℃ under nitrogen protection, triethylamine (1.30 g,0.0128 mol) was added, trimethylchlorosilane (1.25 g, 0.0115 mol) was added dropwise, and stirring was performed for 2 hours; triethylamine (1.46 g,0.0144 mol) was added dropwise to a dichloromethane solution of sulfamoyl chloride (1.34 g,0.0116 mol), and the mixture was stirred for 1 hour; dilute hydrochloric acid and methanol mixture was added, stirred for 40 minutes, washed with brine to obtain an organic phase, concentrated to dryness, and added with ethyl acetate (20 ml) for crystallization to obtain compound i (2.70 g, purity 98%, molar yield 74%).
Example 4
A preparation method for synthesizing doripenem side chain intermediate comprises the following reaction processes:
Figure SMS_11
the method comprises the following specific steps: dissolving a compound II (10.00 g,0.0408 mol) in dichloromethane (100 ml), cooling to below-5 ℃, then adding triethylamine (6.19 g,0.0612 mol) and stirring for 5 minutes, dropwise adding methylsulfonyl chloride (5.61 g,0.0490 mol) for hydroxymethyl esterification, adding water after the reaction is finished for quenching reaction, layering, concentrating an organic layer, adding ethyl acetate (50 ml) into a concentrate for crystallization to obtain a compound III (11.61 g, purity 98% and molar yield 88%);
dissolving a compound III (10.00 g,0.0309 mol) in DMF (80 ml), adding KSAc (5.30 g,0.0464 mol) after dissolving, heating to 50 ℃, keeping the temperature for reaction for 10 hours, slowly pouring the reaction solution into ice water at 0 ℃ after the heat preservation is finished, separating out solid, filtering, washing and drying to obtain a compound IV (8.44 g, purity 98% and molar yield 90%);
dissolving compound IV (8.00 g,0.0264 mol) in a mixed solvent of isopropanol (55 ml) and dichloromethane (11 ml), adding tri-n-butylphosphine (0.27 g,0.0013 mol) into the solution, cooling to-5 ℃, slowly introducing ammonia (0.8 g,0.0470 mol), and reacting for 3h under heat preservation; adjusting pH to 5 with 5% hydrochloric acid, concentrating to dryness, adding ethyl acetate (150 ml) for dissolving, washing with saturated brine, concentrating and crystallizing the organic phase to obtain compound V (5.59 g, purity 98%, molar yield 86%);
compound V (5.00 g,0.0203 mol) was dissolved in THF (50 ml) and borane (0.42 g,0.0305 mol) was added under nitrogen protection at 70℃for 10h; after the reaction, 5ml of methanol was added, the pH=4 was adjusted with hydrochloric acid, the mixture was kept for 3 hours, the layers were separated, the organic layer was concentrated to dryness, and ethyl acetate (20 ml) was added for crystallization to give compound VI (3.3 g, purity 97%, molar yield 70%);
compound vi (3.00 g,0.0129 mol) was dissolved in dichloromethane, cooled to-75 ℃ under nitrogen protection, triethylamine (1.96 g,0.0194 mol) was added, trimethylchlorosilane (1.68 g, 0.0155 mol) was added dropwise, and stirring was carried out for 2 hours after the addition; triethylamine (1.97 g,0.0195 mol) was added dropwise to a dichloromethane solution of sulfamoyl chloride (1.80 g,0.0156 mol), and the mixture was stirred for 1 hour; dilute hydrochloric acid and methanol mixture was added, stirred for 40 minutes, washed with brine to obtain an organic phase, concentrated to dryness, and crystallized by adding ethyl acetate (20 ml) to obtain compound i (2.81 g, purity 97%, molar yield 70%).

Claims (10)

1. A preparation method of a synthetic doripenem side chain intermediate is characterized by comprising the steps of taking a compound IV as a starting material, dissolving the compound IV in an organic solvent I, and introducing ammonia gas in the presence of a protective medium to obtain a compound V;
the structure of the compound IV is as follows:
Figure FDA0004090777790000011
the structure of the compound V is as follows:
Figure FDA0004090777790000012
wherein R is a protecting group on pyrrolidine N;
the protective medium is tri-n-butyl phosphine.
2. The method for preparing the synthetic doripenem side chain intermediate according to claim 1, wherein the preparation method of the compound IV is as follows: reacting the compound III with KSAc at 30-80 ℃ to obtain a compound IV;
the structure of the compound III is as follows:
Figure FDA0004090777790000021
the molar ratio of the compound III to the KSAc is 1 (1-5).
3. The method for preparing the synthetic doripenem side chain intermediate according to claim 1, further comprising the step of carrying out a reduction reaction of the compound V under the action of a carbonyl reducing agent to obtain a compound VI; under the protection of nitrogen and in the presence of an acid binding agent, the compound VI reacts with trimethylchlorosilane and sulfamoyl chloride at the temperature of-80 to-40 ℃ to obtain a compound I;
the structure of the compound VI is as follows:
Figure FDA0004090777790000022
the structural formula of the compound I is as follows:
Figure FDA0004090777790000023
4. the method for preparing the side chain intermediate of synthetic doripenem according to claim 1, wherein the organic solvent I is an alcohol solvent or a mixed solvent containing alcohol, and the mixed solvent comprises an alcohol solvent with better ammonia solubility and a solvent B with better solubility for the compound IV;
the alcohol solvent is one or more of methanol, ethanol, isopropanol and n-butanol; the solvent B is one or more of dichloromethane, chloroform, benzene and toluene; the volume ratio of the alcohol solvent to the solvent B in the mixed solvent is (2-10): 1.
5. The process for the preparation of a synthetic doripenem side chain intermediate according to claim 1, wherein the reaction temperature for the preparation of compound V from compound IV is-10 to 40 ℃.
6. The process for preparing a side chain intermediate of synthetic doripenem as claimed in claim 1, wherein the weight ratio of tri-n-butylphosphine to said compound IV is 1 (20-60).
7. The method for preparing a side chain intermediate of synthetic doripenem according to claim 1, wherein the weight ratio of the ammonia gas to the compound IV is 1 (6-20).
8. A process for the preparation of a synthetic doripenem side chain intermediate according to claim 3, wherein the carbonyl reducing agent is one or more of borane, diborane, sodium borohydride, potassium borohydride and lithium borohydride, and the ratio of the carbonyl reducing agent to the substance of compound v is (0.5-8): 1.
9. The method for preparing the side chain intermediate of synthetic doripenem according to claim 3, wherein the reaction temperature of the reduction reaction is 60-80 ℃, the reaction time is 0.5-24 h, and the reaction solvent is one or more of tetrahydrofuran, methyl tetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, isopropyl ether and dioxane.
10. The method for preparing a side chain intermediate of synthetic doripenem according to claim 1, wherein R is t-butoxycarbonyl, p-nitrobenzoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, allyloxycarbonyl or diisopropylphosphono.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0126587A1 (en) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof
JPS60233076A (en) * 1984-05-03 1985-11-19 Sumitomo Chem Co Ltd Novel beta-lactam and its preparation
CN1071428A (en) * 1991-08-20 1993-04-28 盐野义制药株式会社 Pyrroliaylthiocarbapderivatives derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0126587A1 (en) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof
JPS60233076A (en) * 1984-05-03 1985-11-19 Sumitomo Chem Co Ltd Novel beta-lactam and its preparation
CN1071428A (en) * 1991-08-20 1993-04-28 盐野义制药株式会社 Pyrroliaylthiocarbapderivatives derivatives

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