CN100422184C - Preparation method of meluopeinan - Google Patents
Preparation method of meluopeinan Download PDFInfo
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- CN100422184C CN100422184C CNB2006100833627A CN200610083362A CN100422184C CN 100422184 C CN100422184 C CN 100422184C CN B2006100833627 A CNB2006100833627 A CN B2006100833627A CN 200610083362 A CN200610083362 A CN 200610083362A CN 100422184 C CN100422184 C CN 100422184C
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Abstract
The present invention relates to a preparation method of beta-methylcarbapenem antibiotic-meropenem. Said invention provides its chemical structure formula, and concrete steps of its preparation method.
Description
Technical field
The present invention relates to a kind of preparation method of beta-methylcarbapenem antibiotics, especially relate to the preparation method of meropenem.
Background technology
Up to now, a large amount of natural or synthetic beta-lactamase inhibitor reports has been arranged, on chemical structure, can be divided into oxapenam, penem, carbapenem and monocycle beta-lactam oxapenams, carbapenem wherein, especially beta-methyl carbon penicillenic, as imipenum, meropenem and biapenem many resistant organisms being had fine anti-microbial effect, especially the Type B enzyme is had great restraining effect, is the inhibitor of the inhibition β-Nei Xiananmei of a series of uniquenesses.After finding that sulfomycin has potential antimicrobial acivity to Gram-negative bacteria and gram-positive microorganism, to getting up with the study on the synthesis of proximate carbapenem of sulfomycin or Pennem derivates broad development.
Commercial at present carbapenem and beta-methylcarbapenem antibiotics have SumitomoPharmaceuticals Co., Ltd. (4R, 5S, 6S, 8R2 ' S, 4 ' S)-and 3-[2-dimethylamine carbonyl] pyrrolidyl sulphur]-4-methyl-6-(1-hydroxyethyl)-1-is assorted, and nitrogen dicyclo [3,2,0] hept-2-ene"-7-ketone-2-carboxylic acid (meropenem) is (I);
Merck ﹠amp; Co., the N-formamino sulfomycin (Tienamycin) of Inc. (II);
Lederle Ltd. (1R, 5S, 6S)-and 2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole ammonium-6-yl)] sulphur-6-[R-1-hydroxyethyl]-1-methyl-carbon mould-2-alkene-3-carboxylate salt (III) (biapenem) etc.
Beta-methyl carbon penicillenic parent nucleus synthetic has multiple route, Sumitomo PharmaceuticalsCo. wherein, and the reaction scheme A (USP4933333) of Ltd. is as follows:
The reaction scheme B (USP4990613) of Lederle Ltd. is as follows:
Above-mentioned Sumitomo Pharmaceuticals Co., the route raw material of Ltd. are simple and easy to, but compound (V) has the optically active isomer of a great deal of to need to separate, thereby have influenced yield; The route steps of Lederle Ltd. is corresponding simple, but raw material (XII) is difficult to obtain, and cost is higher.
In 4-mercaptopyrrolidine derivatives (Metro training can side chain) synthetic, Sumitomo PharmaceuticalsCo., Ltd. have adopted reaction scheme C (USP4933333):
This route reaction step is longer, and is difficult to obtain the high purpose product of purity.
From the condensation and the deprotection steps of beta-methylcarbapenem antibiotics parent nucleus and side chain, the condenses purity that most technologies obtain perhaps needs the silicagel column purifying just can obtain the higher condenses of purity about 75%.Remove in the protection step in hydrogenation, generally need to use morpholine propanesulfonic acid (MOPS) buffered soln, and need macromolecule resin to carry out purifying, will have influence on the yield of the finished product (I) like this.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of beta-methylcarbapenem antibiotics-meropenem.This preparation method is easy and simple to handle, product separates easily, content and yield height, save cost, thereby has overcome the deficiencies in the prior art.
The preparation method of meropenem of the present invention may further comprise the steps:
A) make the reaction of formula (IV) compound and formula (XV) compound obtain formula (VI) compound;
B) obtain formula (IX) compound from formula (VI) compound;
C) obtain formula (XI) compound from formula (IX) compound;
D) make the compound of formula (XI) and formula (XX) compound react production (XXIV) compound;
E) make the meropenem of formula (XXIV) compound production (I) under the effect of catalyzer.
In the methods of the invention, adopted the method in three steps " treating different things alike " to obtain formula (XI) compound, concrete step is respectively:
A) make the reaction of formula (IV) compound and formula (XV) compound, obtain formula (XIV) compound; But reaction solution or its enriched material are without separating direct reaction, and making formula (XIV) compound hydrolysis is formula (VI) compound.
Reaction formula is as follows:
In above-mentioned reaction, raw material 4-acetyl heterocyclic butanone (IV) at first with have the α that induces group greatly-bromine propionic acid amide (XV) reaction.The reaction of this step has good stereoselectivity, and the overwhelming majority generates purpose beta configuration product, thereby can improve the deficiencies in the prior art, improves yield.
The first step react available various known method carry out (as, Tanabe Seiyaku Co., Ltd, USP:5,847,115), reaction finishes back separation method difference.Add the little toluene of polarity in reaction solution, the salt pickling organic phase with 4N is a slant acidity to pH then, washes organic phase with salt then, and organic phase solution directly carries out next step.
The available various known method of second step reaction carries out, organic phase solution adding hydrogen peroxide and the lithium hydroxide that also can use the step are hydrolyzed, treatment process after the hydrolysis is earlier with reactant furnishing acidity, tell the water layer that contains a large amount of hydrogen peroxide, and then adjust back to alkalescence, and add sodium sulfite aqueous solution again and reduce remaining hydrogen peroxide, filter out spirocyclic compound then, with the organism in the organic solvent wash water solution, add the hydrochloric acid acid out then and go out compound (VI) crystal.Such two steps comprehensive back yield has had and has significantly improved.
B) make formula (VI) compound reaction production (VII) compound, contain the reaction solution of formula (VII) compound or its enriched material without separating direct reaction production (VIII) compound, contain the reaction solution of formula (VIII) compound or its enriched material without the compound that separates direct reaction production (IX).
Reaction formula is as follows:
In above-mentioned building-up reactions, the first step is reacted available various known method and is carried out (as, authentic reagent method), and the ethyl acetate solution after the reaction treatment directly enters next step without separating.The available various known method of second step reaction carries out, and improvements are direct reaction in above-mentioned solution, and reaction back solution concentrates after treatment, and enriched material directly enters next step without separating.Three-step reaction can carry out with various known method, and reaction back solution concentrates after treatment, crosses silicagel column.Such three steps comprehensive back yield has had and has significantly improved.
C) make formula (IX) compound react the compound of production (X), the reaction solution or the enriched material that contain formula (X) compound generate beta-methyl carbon penicillenic parent nucleus (XI) without separating direct reaction;
Reaction formula is as follows:
In above-mentioned building-up reactions, the first step reaction be selected from ethyl acetate, tetrahydrofuran (THF) and methylene dichloride one or more be solvent, its consumption is 1～10 times of volume of compound (IX), preferred 3～5 times of volumes; With rhodium acetate or sad rhodium is catalyzer, and consumption is 0.1～1% times of equivalent of compound (IX), preferred 0.25～0.5% times of equivalent; Temperature of reaction is 25～100 ℃.
The inert solvent of using in the second step reaction is to be selected from one or more of dioxane, tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile, hexamethylphosphoramide, wherein preferred acetonitrile and dimethyl formamide.
The negatively charged ion that the alkali of using in the reaction generates during for ionization all is the compound of hydroxide ion, comprises various organic basess and mineral alkali, for example mineral alkali and similar alkali such as yellow soda ash, salt of wormwood, sodium hydride, potassium hydride KH; Organic bases and similar alkali such as potassium tert.-butoxide, pyrimidine, various lutidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine.Wherein preferred organic bases is as diisopropylamine, triethylamine, diisopropylethylamine etc.In a preferred embodiment of the invention, select for use diisopropylethylamine as the used alkali of this reaction.
The consumption of alkali should react fully and carry out, every mole 1～2 equivalent compound (IX) normally, preferred every mole 1～1.5 equivalent.
The induced reaction thing of enol ester is a chlorinated diphenyl phosphate, and consumption should react fully and carry out, every mole 1～2 equivalent compound (IX) normally, preferred every mole 1～1.2 equivalent.
Temperature of reaction is-20～50 ℃, preferred-10 ℃～0 ℃.
In the inventive method, step d) is that beta-methyl carbon penicillenic parent nucleus (XI) with 4-mercaptopyrrolidine derivatives (XX) condensation reaction takes place, and its reaction product (XXIV) can be obtained purpose compound (meropenem) through the over hydrogenation deprotection.By above step, can simplify preparation technology, save cost, improve the yield of condenses (XXIV).
In step d), used inert solvent is to be selected from one or more of dioxane, tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile, hexamethylphosphoramide, wherein preferred acetonitrile and dimethyl formamide in the reaction.
The negatively charged ion that generates when used alkali is for ionization in the reaction all is the compound of hydroxide ion, can comprise various organic basess and mineral alkali usually, for example mineral alkali and similar alkali such as yellow soda ash, salt of wormwood, sodium hydride, potassium hydride KH; Organic bases and similar alkali such as potassium tert.-butoxide, pyrimidine, various lutidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine.Wherein preferred organic bases is as diisopropylamine, triethylamine, diisopropylethylamine etc.In a preferred embodiment of the invention, select for use diisopropylethylamine as the used alkali of this reaction.
The consumption of alkali should react fully and carry out, normally every mole 1～2 normal thiol derivative (XX).
The consumption of thiol derivative (XX) should react fully and carry out, can be excessive, but last 1～2 the equivalent on compound (XI) basis normally.
Be reflected under-78 ℃～60 ℃ the temperature and carry out, be preferably-40 ℃～40 ℃.
After reaction was finished, reaction product can obtain with the organic chemistry method separation of routine.
In step e), the reaction of removing protecting group is to adopt catalyzer to carry out catalytic reduction reaction, and described catalyzer can be platinum or palladium carbon.
Used solvent is organic solvent or aqueous organic solvent in the reaction.Described organic solvent is selected from alcohols, ethers, organic acid etc., can be one or more mixture.Wherein alcohols can be selected less alcohols such as methyl alcohol, ethanol for use, and ethers can be selected tetrahydrofuran (THF), dioxane etc. for use; Organic acid can be selected acetate etc. for use.
The negatively charged ion that generates when used alkali is for ionization in the reaction all is the compound of hydroxide ion, can comprise various organic basess and mineral alkali usually, accelerine, 2 for example, organic basess such as 6-lutidine; Mineral alkali such as sodium bicarbonate, saleratus.The alkali that adds in the reaction can be used for adjusting pH, and its add-on is last 1～10 equivalent in compound (XXIV) basis, preferred 1～4 equivalent.
Be reflected in the hydrogen environment of barometric point or pressurization and carry out 0 ℃～100 ℃ of temperature, preferred 0 ℃～40 ℃.
According to a further aspect in the invention, provide the method for preparing meropenem, wherein can adopt the synthetic method for the treatment of different things alike directly to prepare compound (XXIV) by compound (IX), synthetic route be as follows:
The reaction conditions of the reaction conditions reaction same as described above of each step is basic identical in the said synthesis route.For example, obtain containing the reaction solution of formula (XI) compound from formula (IX) compound, this reaction solution or its enriched material are without the compound that separates direct preparation formula (XXIV).
After whole three-step reaction was finished, the separation method of reaction product (XXIV) was:
1, with hydrophobic organic solvent diluting reaction thing, solvent can be selected from one or more of ethyl acetate, methylene dichloride, diisopropyl ether etc.;
2, the phosphate buffer soln that adds pH 5～6 washs organic phase 5～6 times, wash with salt at last, anhydrous magnesium sulfate drying, be directly used in next step raw material after concentrating, the ethyl acetate that also can add 8～15 compounds (IX) equivalent volume, the crystal that adds compound (XXIV) again is as crystal seed, stirred crystallization.
4-mercaptopyrrolidine derivatives among the present invention (Metro training energy side chain), promptly synthetic can the ining all sorts of ways of compound (XX) makes, and preferably made by trans-4-hydroxyl-L-proline(Pro) according to following synthetic route:
1), obtains formula (XV) compound from formula (XXVI) compound;
2), obtain formula (XXI) compound from formula (XV) compound;
3), obtain formula (XXII) compound from formula (XXI) compound;
4), obtain formula (XIX) compound from formula (XXII) compound;
5), obtain formula (XXIII) compound from formula (XIX) compound;
6), obtain formula (XX) compound from formula (XXIII) compound;
Synthetic route is:
Step 1): react available various known method and finish, carry out with amino method on the protection amino acid usually, for example, the method for in the presence of alkali, reacting with nitrobenzyl chloroformate ester.
Step 2): react available various known method and carry out, convert carboxyl to amide group, for example, have active derivative, react in the presence of organic bases with dimethylamine or its hydrochloride then with isopropyl chlorocarbonate reaction formation.
Step 3), 4): react available various known method and finish, hydroxyl is converted to the thiol group of protection; for example, the hydroxyl in (XXI) is converted to active methylsulfonyl ester (XXII), then with various sulphur compound reactions; thioacetic acid potassium for example, triphenyl thiomethyl alcohol etc.
This step also can be finished by the reaction of alcohol derivate and sulphur compound, is reflected in the inert solvent (as tetrahydrofuran (THF) etc.), carries out in the presence of triphenylphosphine and diethyl azodiformate.
Step 5): this step is that sulfur protecting group removes with the oxidation of sulfide and carries out simultaneously, and reaction generates stable company's disulphide crystal (XXIII).Be reflected under the existence of nickel acetate, in inert solvent (as tetrahydrofuran (THF) etc.), carry out.
Step 6): connect disulphide crystal (XXIII) in aqueous organic solvent, be reduced to thiol derivative (XX) with tributylphosphine.
The present invention compared with prior art has the following advantages:
1, in the present invention, compound (XXIV) can be treated different things alike by compound (IX) and be obtained; Compound (IX) can adopt one-pot operation to be got by compound (VI) preparation; Compound (VI) can adopt one-pot operation to get from compound (IV) preparation.This method can make the purpose that originally needs polystep reaction to realize once finish, and has greatly shortened reaction time, has improved labour productivity, facility investment when reducing industrialization, reduce use solvent types and usage quantity, reduced environmental pollution, reduced the production cost of factory.
2, it is easy that preparation method of the present invention is easy and simple to handle, product separates, and the purity and the yield of product significantly improve.
3, in the present invention, raw material is simple and easy to, thereby has saved production cost.
In order to understand essence of the present invention better,,, describe in detail but do not limit the present invention by description to better embodiment of the present invention below in conjunction with accompanying drawing.
Embodiment
The test materials that the present invention is used if no special instructions, is commercially available purchase product.
[embodiment 1] (5R, 6S, 8R, 2 ' S, 4 ' S)-p-nitrobenzyl-3-[4-(1-p-nitro carbobenzoxy-(Cbz)-1-dimethylin carbonyl) pyrrolidyl sulphur]-6-(1-p-nitro carbobenzoxy-(Cbz) oxyethyl group)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XXIV) synthetic
In the bottle of reflux cooler is housed, add the diazonium ketone ester (IX) of 40g (0.102mol) and the ethyl acetate of 200ml, mixture is stirred and heated to 60 ℃, the sad rhodium that adds 140mg, violent stirring is 30 minutes under uniform temp, finish up to diazonium ketone ester (IX) reaction, obtain the solution of 1-Beta-methyl dicyclo ketone ester (X).Reaction solution directly enters next step without separating.
Get the solution of above-mentioned 1-Beta-methyl dicyclo ketone ester (X); add 300ml acetonitrile (dry product); cryosel is bathed and to be cooled to-10～-15 ℃ and use nitrogen protection, adds the diisopropylethylamine of 14.57g (0.113mol) and the diphenyl phosphate chloride of 27.54g (0.102mol) then.Reaction mixture stirs and reacted completely up to 1-Beta-methyl dicyclo ketone ester (X) in 5 hours under uniform temp, obtains 1-Beta-methyl alkenyl phosphoric acid ester (XI) solution.Then, under the reaction mixture uniform temp, add [2S, the 4S]-1-p-nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl-4-mercapto pyrrolidine (XX) of 34g (0.096mol) and the diisopropylethylamine of 15.4g (0.133mol), stirred 5～8 hours.After reaction finished, the gained reaction soln was with the dilution of 500ml ethyl acetate, and with 3.5% SODIUM PHOSPHATE, MONOBASIC solution washing 5 times, the organic phase anhydrous magnesium sulfate drying, underpressure distillation is except that desolvating.Residue is that (HPLC quantitatively is 60g purpose compound to 75g, yield 84%) can be directly used in next step reaction, also can add the 250ml ethyl acetate, add crystal seed, stirred 3～5 hours down at 10～15 ℃, then there is a large amount of crystal to separate out, filter and collect crystal, dry, obtain (5R, 6S, the 8R of 53.4g (yield 75%), 2 ' S, 4 ' S)-p-nitrobenzyl-3-[4-(1-p-nitro carbobenzoxy-(Cbz)-1-dimethylin carbonyl) pyrrolidyl sulphur]-6-(1-p-nitro carbobenzoxy-(Cbz) oxyethyl group)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XXIV) crystal.
The determination of physical appearance result of compound (XXIV):
IR
max neat(cm
-1)：1780，1745，1705，1650，1605，1515，1342，1257.
NMR δ (CDCl
3): 1.49 (3H, d, J=6Hz), 2.99 (3H, s), 3.11 (3H, s), 5.25 (4H, s), 5.23 and 5.46 (2H, ABq, J=14Hz), 7.53 (4H, d, J=8.5Hz), 7.62 (2H, d, J=8.5Hz), 8.18 (6H, d, J=8.5Hz).
[α]
D 28+ 7.7 ° (c=0.303, acetone)
[embodiment 2] (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-(1-hydroxyethyl)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid (I) synthetic
With (5R, 6S, 8R, 2 ' S, 4 ' S)-p-nitrobenzyl-3-[4-(1-p-nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl)-pyrrolidyl sulphur]-6-(1-p-nitro carbobenzoxy-(Cbz) oxyethyl group)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XXIV) (be previous step concentrate oily matter) 15g (HPLC quantitatively is 12.5g) is dissolved in the 250ml tetrahydrofuran (THF), stirs to add 200ml water down.This solution is placed the autoclave of 1L, stir then and add 2 of 5.5g, the 10% palladium carbon of 6-lutidine and 2g down.The gained mixture carried out hydrogenation 1 hour under the hydrogen-pressure of 1.8MPa.Remove by filter catalyzer, filtrate is used the acetone diluted of 800ml, then, add crystal seed down at 5～15 ℃, there is mass crystallization to separate out after 30 minutes, under uniform temp, drip the acetone of 400ml again, stirred 30 minutes, filter and gather crystal, and with 50ml washing with acetone crystal, 40 ℃ of following vacuum-dryings obtain (5R, the 6S of 5.1g (yield 65%), 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-trihydrate of 6-(1-hydroxyethyl)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid (I), pale yellow crystals.
The determination of physical appearance result of compound (I):
UV
max H2Onm：297
IR
max KBrcm
-1：1755，1627，1393，1252，1130.
NMRδ(D
2O)：1.25(3H，d，J＝6.4Hz)，1.81-1.96(1H，m)，2.96(3H，s)，3.03(3H，s)，3.14-3.20(3H，m)，3.31-3.41(2H，m)，3.62-3.72(1H，m)，3.90-4.00(1H，m)，4.14-4.26(2H，m)，4.63(1H，t，J＝8.5Hz).
[embodiment 3] (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-(1-hydroxyethyl)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid (I) synthetic
With (5R, 6S, 8R, 2 ' S, 4 ' S)-p-nitrobenzyl-3-[4-(1-p-nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl)-pyrrolidyl sulphur]-6-(1-p-nitro carbobenzoxy-(Cbz) oxyethyl group)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XXIV) 10g (crystallisate) is dissolved in the 250ml tetrahydrofuran (THF), stirs to add 200ml water down.This solution is placed the autoclave of 1L, stir then and add 2 of 5.5g, the 10% palladium carbon of 6-lutidine and 2g down.The gained mixture carried out hydrogenation 1 hour under the hydrogen-pressure of 1.8MPa.Remove by filter catalyzer, filtrate is used the acetone diluted of 800ml, then, add crystal seed down at 5～15 ℃, there is mass crystallization to separate out after 30 minutes, under uniform temp, drip the acetone of 400ml again, stirred 30 minutes, filter and gather crystal, and with 50ml washing with acetone crystal, 40 ℃ of following vacuum-dryings obtain (5R, the 6S of 4.5g (yield 71.8%), 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-trihydrate of 6-(1-hydroxyethyl)-1-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid (I), pale yellow crystals.
The determination of physical appearance result of compound (I):
UV
max H2Onm：297
IR
max KBrcm
-1：1755，1627，1393，1252，1130.
NMRδ(D
2O)：1.25(3H，d，J＝6.4Hz)，1.81-1.96(1H，m)，2.96(3H，s)，3.03(3H，s)，3.14-3.20(3H，m)，3.31-3.41(2H，m)，3.62-3.72(1H，m)，3.90-4.00(1H，m)，4.14-4.26(2H，m)，4.63(1H，t，J＝8.5Hz).
[embodiment 4] (3S, 4R)-3-[(1R)-the 1-hydroxyethyl]-4-[(1R)-1-methyl-3-diazonium-3-PNB oxygen carbonyl-2-ketone group propyl group]-heterocyclic fourth-2-ketone (IX) synthetic
The heterocyclic butanone carboxylic acid (VI) of 25g (86mmol) is joined in the anhydrous acetonitrile of 300ml, stirring the carbonyl dimidazoles mixture that adds 17.5g (110mmol) down at room temperature stirred 30 minutes, the anhydrous propanedioic acid list that adds 55.5g (110mmol) then is to nitrobenzyl ester magnesium salts, and reaction mixture stirred 18 hours at 25～35 ℃.After reaction finishes, the hydrochloric acid that under agitation adds the 1N of the ethyl acetate of 450ml and 450ml in the reaction mixture, make water pH 2～3, organic phase is thoroughly washed with salt solution, 5% wet chemical, salt solution respectively, obtain (3S, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-4-[(1R)-1-methyl-3-PNB oxygen carbonyl-2-ketone group propyl group]-ethyl acetate solution of heterocyclic fourth-2-ketone (VII), can carry out next step without separating.
The methyl alcohol that adds 100ml at the ethyl acetate solution of the above-mentioned silica-based keto ester of uncle's O-fourth dimethyl (VII), then at 20～25 ℃ of 6N hydrochloric acid that add 100ml, reaction mixture stirred 2 hours under uniform temp, reaction finishes the saturated brine that the back adds 500ml, organic phase is used 10% the Sodium phosphate dibasic washing of 2 * 500ml again, saturated brine washing then, anhydrous magnesium sulfate drying, vacuum concentration, enriched material be mainly (3S, 4R)-3-[(1R)-the 1-hydroxyethyl]-4-[(1R)-1-methyl-3-PNB oxygen carbonyl-2-ketone group propyl group]-heterocyclic fourth-2-ketone (VIII).Can carry out next step without separating.
Above-mentioned enriched material adds the acetonitrile of 140ml, after the stirring and dissolving, at 0～5 ℃ of triethylamine that adds 30.3g (86mmol) to dodecyl sulfonyl azide and 9.6g (95mmol), reaction mixture stirred 2 hours, the hydrochloric acid 220ml agitator treating that adds 0.5N, organic phase is water completely, the salt water washing, anhydrous magnesium sulfate drying, vacuum concentration, the oily matter that obtains with the silica gel of 250ml carry out column chromatography (elutriant is ethyl acetate-sherwood oil=2: 1 (V/V)) obtain light yellow crystal 25g (yield 77.2%) for (3S, 4R)-3-[(1R)-the 1-hydroxyethyl]-4-[(1R)-1-methyl-3-diazonium-3-PNB oxygen carbonyl-2-ketone group propyl group]-heterocyclic fourth-2-ketone (IX).
The determination of physical appearance result of compound (IX):
[α]
D 21＝-50.4°(c＝2.5，CH
2Cl
2)
IR
max KBrcm
-1：2140，1750，1q720，1650.
NMRδ(CDCl
3)：1.22(3H，d，J＝6.0Hz)，1.32(3H，d，J＝6.0Hz)，2.38(1H，d，J＝3.2Hz)，2.92(1H，dd，J＝2.4，7.6Hz)，3.77(1H，m)，3.86(1H，m)，4.15(1H，m)，5.38(2H，s).5.90(1H，s)，7.57and?8.30(2H，m).
[embodiment 5] (3S, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-4-[(1R)-1-methyl isophthalic acid-propyloic]-heterocyclic fourth-2-ketone (VI) synthetic
The zinc powder of 34g (0.523) is added in the anhydrous tetrahydro furan of 60ml, be heated under stirring and boil, add 50g (0.174mol) (3S then, 4R)-the 4-acetoxy-3-[(1R)-and the 1-tert-butyl dimethyl silica ethyl] heterocyclic fourth-2-ketone (IV) and 90g (0.256mol) 3-(2-bromopropyl)-spiral shell [2,3-dihydro-4H-1,3-benzoxazine-2,1 '-cyclohexyl]-4-ketone (XV) is dissolved in the mixing solutions that the anhydrous tetrahydro furan of 180ml forms, adding speed with reaction solution not bumping be advisable, add the back and refluxed 30 minutes, be cooled to room temperature, add 5g diatomite in the reaction mixture, the reaction mixture suction filtration, filter residue washs with an amount of tetrahydrofuran (THF), merging filtrate and washing lotion, the toluene that adds 60ml, add the 2N hydrochloric acid of 200ml in this mixture, regulating pH is 5～6, organic phase salt solution washed twice.Be 3-{ (2R)-2-[(3S, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-2-ketone group heterocyclic fourth-4-yl] propyl group }-tetrahydrofuran (THF)-toluene solution of spiral shell [2,3-dihydro-4H-1,3-benzoxazine-2,1 '-cyclohexyl]-4-ketone (XIV).This mixture enters next step without separation.
Add the tetrahydrofuran (THF) of 150ml in the above-mentioned reaction mixture, temperature is controlled at 5～15 ℃, stirs the hydrogen peroxide that adds 96g 30% down, adds the Lithium Hydroxide Monohydrate of 21g again, and stirring reaction is 3 hours under uniform temp.After reaction finished, the 4N hydrochloric acid adjusting pH that reaction mixture under agitation adds about 130ml was 2, organic phase salt water washing 3 times.It is 10 that organic phase is regulated pH at the sodium hydroxide that adds about 200ml 6% under 5～15 ℃ of stirrings, adds 17% S-WAT about 50ml then to the nondiscoloration of solution starch KI test paper.Suction filtration, filter residue wash with water 3～4 times, merging filtrate and washing lotion.Water is washed 3～4 times with ethyl acetate again, vacuum is drained the ethyl acetate of clean aqueous phase, reaction mixture adds 4N hydrochloric acid to regulate pH is 2 under 5～15 ℃ of stirrings then, there is mass crystallization to separate out, under uniform temp, stirred 2 hours, filter, wash crystal with water, drying, obtain 46g (yield 87.7%) (3S, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-4-[(1R)-1-methyl isophthalic acid-propyloic]-heterocyclic fourth-2-ketone (VI) white crystals.
The determination of physical appearance result of compound (VI):
Mp：146～147℃
IR
max neat(cm
-1)：1740，1465，1330，1255，1043，837.
NMR:0.08 (6H, s), 0.7 (9H, s), 1.24 (3H, d, J=7), 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, wide).
[embodiment 6] (2S, 4R)-2-dimethylamine carbonyl-4-acetylthio-1-PNZ-tetramethyleneimine (XIV) synthetic
1, anti-form-1-(p-nitro carbobenzoxy-(Cbz))-4-hydroxyl-L-proline(Pro) (XV) is synthetic
The L-oxyproline (XXIV) of 26.2g (0.20mol) is under agitation joined in the 220ml 2N sodium hydroxide solution, lower the temperature 0～5 ℃, the nitrobenzyl chloroformate ester that drips 47.3g (0.22mol) is dissolved in the solution in the methylene dichloride of 40ml, under uniform temp, stirred 1 hour, tell the methylene dichloride phase then, water is used the washed with dichloromethane of 70ml again, water uses the vitriol oil of 36.6g 0～5 ℃ of acidifying, there is a large amount of crystallizations to separate out, suction filtration is collected crystallization, and washes drying with water, obtain 57.8g compound (XV) (yield 93%), fusing point: 134～135.5 ℃.
2, (2S, 4R)-2-dimethylamine carbonyl-4-hydroxyl-1-PNZ-tetramethyleneimine (XVI) synthetic
The compound (XV) of 31.0g (0.1mol) is joined in the methylene dichloride of 150ml, stir the triethylamine that adds 15.2g (0.15mol) down.At-10～0 ℃, drip the isopropyl chlorocarbonate of 18.4g (0.15mol), mixture stirred 1 hour under uniform temp, the Dimethylammonium chloride that adds 16.3g (0.20mol) then at-10～0 ℃, drips the triethylamine of 30.3g (0.30mol), after adding, stirred 1 hour.Reaction mixture is used 1N hydrochloric acid up hill and dale, salt solution, 5% sodium bicarbonate, the salt washing, anhydrous magnesium sulfate drying filters the elimination siccative, obtain (2S, 4R)-dichloromethane solution of 2-dimethylamine carbonyl-4-hydroxyl-1-PNZ-tetramethyleneimine (XVI), enter next step without separation.
3, (2S, 4R)-2-dimethylamine carbonyl-4-mesyloxy-1-PNZ-tetramethyleneimine (XVII) synthetic
At the last triethylamine that adds 21.8g (0.24mol) in the dichloromethane solution that obtains compound (XXI) that goes on foot, at-10～0 ℃, drip the methylsulfonyl chloride of 16.8g (0.15mol), mixture stirred 1 hour under uniform temp then.Reaction mixture is used salt solution up hill and dale, 5% sodium bicarbonate, the salt washing, anhydrous magnesium sulfate drying filters the elimination siccative, solvent removed in vacuo, enriched material is used methyl alcohol-sherwood oil (2: 1, v/v) recrystallization obtains 29.8g compound (XVII) (yield 73%) white crystal, fusing point: 115～116 ℃.
4, (2S, 4R)-2-dimethylamine carbonyl-4-acetylthio-1-PNZ-tetramethyleneimine (XIX) synthetic
The compound (22) of 20.8g (0.05mol) and the thioacetic acid potassium of 8.55g (0.075mol) are joined in the mixed solvent of 60ml DMF and 60ml toluene, 65～70 ℃ of stirring reactions 6 hours.Cooling then, reaction mixture with the toluene extraction of 100ml, merges organic phase again with 300ml toluene and the dilution of 200ml water, water, with salt washing back anhydrous magnesium sulfate drying, removes by filter siccative, solvent removed in vacuo, enriched material carries out next step without separation.
[embodiment 7] (2S, 4R)-2-dimethylamine carbonyl-4-sulfydryl-1-PNZ-tetramethyleneimine (XX) synthetic
(2S in the 4th step of embodiment 5,4R)-add the tetrahydrofuran (THF) of 200ml in 2-dimethylamine carbonyl-4-acetylthio-1-PNZ-tetramethyleneimine (XIX) enriched material, add 15g (60mmol) four water acetic acid nickel, stirring and reflux 2 hours, cooling after reacting completely adds toluene 100ml, then water, the salt water washing, the organic phase anhydrous magnesium sulfate drying, vacuum distilling removes and desolvates, and adds 150ml methyl alcohol again, stirring is cooled to about 10 ℃, a large amount of throw outs are then arranged, filter drying, 15g (yield is 85%) to two [(2S, 4R)-2-dimethylamine carbonyl-1-PNZ-tetramethyleneimine-4-yl] disulphide (XXIII) buff powder.
MS：M+1＝705
IR：cm
-11705，1650，1515
1H?NMR(CDCl
3)：1.90(1H，d)，2.97(3H，s)，3.08(3H，s)，5.19(2H，s)，7.48(2H，d)，8.15(2H，d)。
With the two [(2S of 15g (21mmol); 4R)-and 2-dimethylamine carbonyl-1-PNZ-tetramethyleneimine-4-yl] disulphide (XXIII) is suspended in the mixed solvent of 80ml tetrahydrofuran (THF) and 80ml water; under nitrogen protection and stirring, drip the positive tributylphosphine of 6g (60mmol); stir reacted completely in 30 minutes after; add 100ml ethyl acetate and 200ml water; behind the agitator treating; the organic phase anhydrous magnesium sulfate drying; vacuum distilling removes and desolvates; enriched material adds the 100ml ethyl acetate; stirred crystallization; treat the sherwood oil of Dropwise 5 0ml behind the mass crystallization, filter and collect crystal, drying; obtain 13.5g (yield 90%) (2S, 4R)-2-dimethylamine carbonyl-4-sulfydryl-faint yellow crystallization of 1-PNZ-tetramethyleneimine (XX).
The determination of physical appearance result of compound (XX):
Mp：118.5～119.5℃
[α]
D 20＝+9.60°(c＝1.0，CHCl
3)
MS：M+1＝354
IR：cm
-11705，1650，1515
1H?NMR(CDCl
3)：1.90(1H，d)，2.97(3H，s)，3.08(3H，s)，5.19(2H，s)，7.48(2H，d)，8.15(2H，d)。
More than the description of better embodiment of the present invention is not limited the present invention, those skilled in the art can make various changes or distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (11)
1. the preparation method of a meropenem comprises the steps:
A) make the reaction of formula (IV) compound and formula (XV) compound obtain formula (VI) compound;
B) obtain formula (IX) compound from formula (VI) compound;
C) obtain formula (XI) compound from formula (IX) compound;
D) make the compound of formula (XI) and formula (XX) compound react production (XXIV) compound;
E) make the meropenem of formula (XXIV) compound production (I) under the effect of catalyzer;
Synthetic route is:
2. the described preparation method of claim 1 is characterized in that in the described method, and formula (XI) compound that described step c) obtains is without separating directly and formula (XX) compound prepared in reaction formula (XXIV) compound.
3. the described preparation method of claim 1, it is characterized in that making the reaction of formula (IV) compound and formula (XV) compound after, add toluene in reaction solution, and be slant acidity to pH with the salt pickling of 4N; Adding hydrogen peroxide and lithium hydroxide are hydrolyzed in this solution then, earlier with reactant furnishing acidity, tell the water layer that contains a large amount of hydrogen peroxide after the hydrolysis; Again this water layer is adjusted back to alkalescence, add sodium sulfite aqueous solution and reduce remaining hydrogen peroxide; Filter at last, the organism with in the organic solvent flush away filtrate adds hydrochloric acid and separates out formula (VI) compound.
4. the described preparation method of claim 1, it is characterized in that in the described step c), in organic solvent, in the presence of catalyzer, make the reaction of formula (IX) compound generate 1-Beta-methyl dicyclo ketone ester (X), wherein said organic solvent is selected from one or more of ethyl acetate, tetrahydrofuran (THF), methylene dichloride, and its consumption is 1～10 times of volume of formula (IX) compound; Described catalyzer is rhodium acetate or sad rhodium, and its consumption is 0.1～1% times of equivalent of the compound of formula (IX), and temperature of reaction is 25～100 ℃; Then, in containing the inert solvent of organic bases, make formula (X) compound and chlorinated diphenyl phosphate reaction production (XI) compound, wherein said inert solvent is selected from one or more of dioxane, tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile, hexamethylphosphoramide, the consumption of described organic bases is 1～2 times of formula (IX) compound molar weight, temperature of reaction is-15 ℃～0 ℃, and the consumption of described chlorinated diphenyl phosphate is 1～2 times of formula (IX) compound molar weight.
5. the described preparation method of claim 1, it is characterized in that described step d) is reflected in the alkaliferous inert solvent carries out, temperature of reaction is-78 ℃～60 ℃, inert solvent is to be selected from one or more of dioxane, tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile, hexamethylphosphoramide, and alkali is organic bases.
6. the described preparation method of claim 1, it is characterized in that described step e) is reflected in the alkaliferous solvent carries out, and temperature of reaction is 0 ℃～100 ℃, and described solvent is organic solvent or aqueous organic solvent; Catalyzer is platinum or palladium carbon, is reflected in the hydrogen environment of barometric point or pressurization to carry out.
7. the described preparation method of claim 2, it is characterized in that obtaining containing from formula (IX) compound in the described method reaction solution of formula (XI) compound, this reaction solution or its enriched material are directly used in the compound of preparation formula (XXIV) without separation, be reflected in the alkaliferous inert solvent and carry out, temperature of reaction is-78 ℃～60 ℃.
8. the described preparation method of claim 1 is characterized in that the preparation process of described formula (XX) compound comprises:
1) obtains formula (XV) compound from formula (XXVI) compound;
2) obtain formula (XXI) compound from formula (XV) compound;
3) obtain formula (XXII) compound from formula (XXI) compound;
4) obtain formula (XIX) compound from formula (XXII) compound;
5) obtain formula (XXIII) compound from formula (XIX) compound;
6) obtain formula (XX) compound from formula (XXIII) compound;
Synthetic route is:
9. the described preparation method of claim 8 is characterized in that in the described step 5), is reflected in the inert solvent that contains nickel acetate and carries out; In the described step 6), the compound of formula (XXIII) is reduced to the compound of formula (XX), is reflected in the aqueous organic solvent and carries out with tributylphosphine.
10. claim 1 or 2 described preparation methods is characterized in that the separation method of described formula (XXIV) compound is:
With hydrophobic organic solvent diluting reaction thing, with be selected from ethyl acetate, methylene dichloride, diisopropyl ether one or more be solvent, the phosphate buffer soln that adds pH 5～6 washs organic phase 5～6 times, wash with salt then, anhydrous magnesium sulfate drying is directly used in the raw material of next step reaction after concentrating.
11. the described preparation method of claim 10, the separation method that it is characterized in that described formula (XXIV) compound further comprises the step of formula (XXIV) compound crystal that will obtain.
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| CN101328178B (en) * | 2007-06-15 | 2010-10-13 | 山东轩竹医药科技有限公司 | Penem derivates containing thiophen substituted sulfhydryl pyrrolidine |
| CN101891746B (en) * | 2008-08-29 | 2012-06-27 | 深圳市海滨制药有限公司 | Preparation method for meropenem |
| CN101348486B (en) * | 2008-08-29 | 2010-09-29 | 深圳市海滨制药有限公司 | Preparation of meropenem |
| CN101891742B (en) * | 2010-07-20 | 2012-06-27 | 深圳市海滨制药有限公司 | Preparation method of meropenem trihydrate crystal |
| CN101914098B (en) * | 2010-07-20 | 2012-08-15 | 深圳市海滨制药有限公司 | Preparation method of Meropenem trihydrate crystals |
| CN101891743B (en) * | 2010-07-20 | 2012-08-15 | 深圳市海滨制药有限公司 | Method for synthesizing meropenem intermediate |
| CN101955482B (en) * | 2010-09-18 | 2012-03-21 | 景德镇市富祥药业有限公司 | Method for preparing protected meropenem |
| CN102153554A (en) * | 2010-09-21 | 2011-08-17 | 重庆天地药业有限责任公司 | Method for preparing meropenem |
| CN102532140B (en) * | 2010-12-21 | 2015-03-11 | 北大方正集团有限公司 | Method for preparing meropenem trihydrate |
| WO2012097471A1 (en) * | 2011-01-18 | 2012-07-26 | 深圳市海滨制药有限公司 | PREPARATION METHOD OF β-METHYL CARBAPENEM COMPOUND |
| CN102250033A (en) * | 2011-05-27 | 2011-11-23 | 菏泽睿智科技开发有限公司 | Preparation method for novel chiral auxiliary of synthetic imipenem antibiotic |
| CN102249972A (en) * | 2011-05-27 | 2011-11-23 | 菏泽睿智科技开发有限公司 | Method for synthesizing novel chiral lateral chain of meropenem |
| CN102250096B (en) * | 2011-09-05 | 2016-04-06 | 江西华邦药业有限公司 | A kind of preparation method of meropenem |
| CN102908344A (en) * | 2012-08-24 | 2013-02-06 | 海口市制药厂有限公司 | Pharmaceutical composition comprising meropenem, and preparation method and application therof |
| CN102977134A (en) * | 2012-12-13 | 2013-03-20 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of carbapenem intermediate beta-methyl-ADC-8 |
| CN106631958B (en) * | 2016-12-28 | 2019-10-11 | 江西如益科技发展有限公司 | The preparation method of two sulphur object of Meropenem side chain |
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