CN101891746A - Preparation method for meropenem - Google Patents
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Abstract
The invention provides a preparation method for meropenem, which comprises the following steps of: 1) reacting a compound shown as a formula (XVI) with a compound shown as a formula (XVII) to prepare a compound shown as a formula (XVIII); 2) reacting the compound shown as the formula (XVIII) with an organophosphorus reagent to prepare ylide, and preparing a compound shown as a formula (XIX) under the action of a catalyst phenol or hydroquinone; 3) hydrolyzing the compound shown as the formula (XIX) to obtain a compound shown as a formula (XX); and 4) reducing the compound shown as the formula (XX) to prepare the meropenem shown as a formula (I) under the action of the catalyst and hydrogen. The method has the advantages of short synthetic route, simple and convenient operation, simple and readily available raw materials and no need of a noble metal rhodium catalyst.
Description
The application is dividing an application of Chinese patent application CN200810142137.5.
Technical field
The present invention relates to the preparation method of a kind of Beta-methyl carbapenem antibiotic (Carbapenem), especially relate to the preparation method of meropenem (Meropenem).
Background technology
With meropenem (I) (Sumitomo Pharmaceuticals Co., Ltd.), imipenum (II) (Merck﹠amp; Co., Inc.) and biapenem (III) (Lederle Ltd.) etc. for the carbapenem antibiotic of representative with its broad-spectrum antibacterial activity, from it is found, obtained extremely widely paying attention to, sought preparation method efficiently and be always one of the research emphasis of educational circles and industrial community and focus.
Through effort for many years, the preparation of Beta-methyl carbapenem antibiotic parent nucleus has at present developed and several different methods.Wherein, representational synthetic route mainly contains following two:
First Sumitomo Pharmaceuticals Co., the reaction scheme A (USP4933333) of Ltd. company, as follows:
It two is the reaction scheme B (USP4990613) of Lederle Ltd. company, and is as follows:
Route A raw material is easy to get, and has obtained widespread use at present, but since this reaction scheme long and have multiple intermediate particularly chiral intermediate need to separate, do not meet the requirement of Atom economy, brought certain trouble to operation, environment has also been caused pollution; In addition, owing to need use the compound as catalyst of Noble Metal Rhodium when synthetic compound (X), along with the shortage and the price of Noble Metal Rhodium grows to even greater heights, the preparation cost of this route also grows to even greater heights, and is not a comparatively ideal preparation method.
Though route B is short than route A, because raw material (XII) is difficult for acquisition, and the existence defective identical with route A, still not a kind of preparation method preferably.
On above-mentioned two kinds of preparation methods' basis, the method that Chinese patent application 200610083362.7 had once developed a kind of three steps " treating different things alike " prepares meropenem (I) (as follows), though this method has adopted the method in three steps " treating different things alike " to prepare compound (XI), simplified operation, reduced the separation number of times of intermediate, but in the process of synthetic compound (XI), still need to use the compound as catalyst of expensive Noble Metal Rhodium, preparation cost is still higher, is unfavorable for Sustainable development.
Summary of the invention
The technical problem to be solved in the present invention provides that a kind of synthesis step is short, easy and simple to handle, product is easily separated, yield is high, has avoided the use of Noble Metal Rhodium catalyzer, to the novel method of the less preparation meropenem (I) of the influence degree of environment.
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of meropenem, comprise the steps:
1) make the reaction of formula (XVI) compound and formula (XVII) compound obtain formula (XVIII) compound;
2) make the reaction of formula (XVIII) compound and organophosphorus reagent generate ylide, under the effect of catalyzer phenol or Resorcinol, prepare formula (XIX) compound then;
3) make formula (XIX) compound hydrolysis obtain formula (XX) compound;
4) make formula (XX) compound reduction production (I) meropenem under catalyzer and hydrogen effect;
Reaction scheme is:
In preparation method of the present invention, described formula (XVI) compound can perhaps be buied by commercial sources according to known in the art or unknown any means preparation.For example, preparation comprises the steps: by the following method
I) make the reaction of formula (IV) compound and formula (XIV) compound obtain formula (VI) compound;
Ii) make formula (VI) compound and formula (XV) compound reaction production (XVI) compound;
Reaction scheme is:
Above-mentioned steps 1) in, formula (XVI) compound and chlorine oxalic acid react in organic solvent under the effect of alkali nitrobenzyl ester (XVII), with higher yields production (XVIII) compound.Chlorine oxalic acid was to nitrobenzyl ester (XVII) and mol ratio formula (XVI) compound normally 1.5～3: 1, first-selected 2: 1.Used alkali can be mineral alkali, as sodium hydroxide, sodium hydride, yellow soda ash, sodium bicarbonate, sodium hydrogen phosphate, potassium hydroxide, salt of wormwood, saleratus, potassium hydrogen phosphate, potassium hydride KH etc.; Also can be organic bases, as pyridine, triethylamine, diisopropyl ethyl amine (DIPEA), 4-Dimethylamino pyridine (DMAP), 2,6-lutidine etc., preferred organic bases pyridine.The consumption of alkali should react fully and carry out, and alkali and chlorine oxalic acid were to the mol ratio of nitrobenzyl ester (XVII) normally 1～2: 1, first-selected 1.5: 1.Used organic solvent is selected from toluene, ethyl acetate, tetrahydrofuran (THF) (THF), dioxane, methyl tert-butyl ether, methyl-phenoxide, methylene dichloride, trichloromethane, acetone, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMAc), acetonitrile etc., preferred toluene.Reaction times is 1～3 hour, and temperature of reaction is-20～5 ℃, preferred-10～0 ℃.The not purified the next step that is directly used in of products therefrom crude product, solvent is capable of circulation applying mechanically after simple the recovery.
In above-mentioned steps 2) in, formula (XVIII) compound reacts in inert solvent with organophosphorus reagent earlier and generates phosphorus ylide, closes ring through the Wittig reaction again under the effect of catalyzer and generates meropenem precursor compound (XIX).The used organophosphorus reagent of this reaction can be chosen in organophosphorus reagents such as triphenyl phosphorus, three normal-butyl phosphorus, triethyl-phosphite, trimethyl phosphite, triisopropyl phosphite, methyl acid phosphate diethyl ester, preferred triethyl-phosphite and trimethyl phosphite.The consumption of organophosphorus reagent should react fully and carry out, the mol ratio of organophosphorus reagent and formula (XVIII) compound normally 2～10: 1, first-selected 2.5: 1.Catalyzer can be chosen in phenol and Resorcinol, preferred Resorcinol.Inert solvent can be selected from not the solvent with the organophosphorus reagent reaction, as saturated alkane (normal heptane, octane etc.), chooses in the aromatic hydrocarbon (toluene, dimethylbenzene etc.), preferred dimethylbenzene.Reaction can be carried out to nitrogen pressure at normal pressure, preferred normal pressure.Reaction times was advisable with 5～12 hours.After reaction finished, the concentrating under reduced pressure reaction solution reclaimed solvent, and the products therefrom crude product is behind the re-crystallizing in ethyl acetate purifying, and purity and content can reach more than 97%.Reaction and recrystallization solvent for use be capable of circulation applying mechanically after simple the recovery.
In above-mentioned steps 3) in, formula (XIX) compound under the mixture effect of acid, fluorochemicals or fluorochemicals and acid in organic solvent hydrolysis silicon ehter bond, with higher yields generation meropenem precursor formula (XX) compound.Described acid can be mineral acid, as dilute hydrochloric acid, hydrofluoric acid etc., also can be organic acid, as acetic acid; Fluorochemicals can be ammonium bifluoride etc., fluorochemicals and the preferred tetrabutyl ammonium fluoride of combination (TBAF) of acid and the combination of acetic acid.Used organic solvent can be selected tetrahydrofuran (THF), acetone, N for use, dinethylformamide, methylene dichloride, ethyl acetate, N-Methyl pyrrolidone etc., preferred tetrahydrofuran (THF).Temperature of reaction is 0～40 ℃, first-selected room temperature.Reaction times is 24～72 hours.Solvent for use is capable of circulation applying mechanically after simple the recovery.Product is without being further purified direct input the next step.
In above-mentioned steps 4) in, be the catalytic reduction reaction that under the effect of catalyzer and hydrogen, carries out by the target compound of formula (XX) compound production (I), catalyst system therefor is palladium, palladium/carbon or palladium hydroxide, preferred palladium/carbon.Used solvent is organic solvent or water-containing organic solvent in the reaction, and described organic solvent is selected from alcohols, ethers, organic acid etc., can be one or more mixture.Wherein, alcohols is selected from methyl alcohol, ethanol etc.; Ethers is selected from tetrahydrofuran (THF), dioxane etc.; 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, usually can comprise organic bases and mineral alkali, as accelerine, N-methylmorpholine, diisopropyl ethyl amine, 2,6-lutidine, sodium bicarbonate, potassium hydrogen phosphate etc.The alkali that adds in the reaction can be used for the pH value of conditioned reaction liquid, and the mol ratio of alkali and formula (XX) compound is generally 1～10: 1, preferred 1～4: 1.Be reflected in barometric point or the hydrogenation environment and carry out, temperature is 0～100 ℃, preferred 0～40 ℃.
In the preparation method of formula (XVI) compound,
Step I) in, formula (IV) compound with have the α that induces group greatly-bromine propionic acid amide (XIV) reaction and have good stereoselectivity, the overwhelming majority generates the beta configuration product, the present invention adopts the method for Chinese patent application 200610083362.7, adopt the synthetic method of " treating different things alike " to prepare formula (VI) compound from formula (IV) compound, adopt the synthetic method of " treating different things alike " to prepare formula (VI) compound from compound (IV), promptly with synthetic 3-{ (the 2R)-2-[(3S that contains of known method, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-2-carbonyl azetidin-4-yl] propyl group }-spiral shell [2,3-dihydro-4H-1,3-benzoxazine-2,1 '-cyclohexyl]-reaction solution of 4-ketone, this reaction solution is directly used in next step reaction without separation, with its resultant hydrolysis production (VI) compound.
Step I i) in, formula (VI) compound and formula (XV) compound are at N, in organic solvent, react under the effect of N '-carbonyl dimidazoles (CDI) or two cyclohexanediamine (DCC) and 4-Dimethylamino pyridine (DMAP), generate formula (XVI) compound that has the meropenem side chain with higher yields.Reaction times is 2～12 hours, and temperature of reaction is 0～40 ℃, preferred room temperature.Used organic solvent can be selected from acetone, acetonitrile, toluene, dimethylbenzene, ethyl acetate, tetrahydrofuran (THF), isopropyl ether, methyl tert-butyl ether, methyl-tert butanone, methylene dichloride, trichloromethane etc., preferred methylene dichloride.The not purified the next step that is directly used in of products therefrom crude product, solvent is capable of circulation applying mechanically after simple the recovery.
The present invention compared with prior art has following advantage:
1, synthetic route is shorter, and is easy and simple to handle.In the present invention, by formula (XVI) compound is raw material, only need just can obtain meropenem (I) through four-step reaction, and traditional route is (as SumitomoPharmaceuticals Co., Ltd. reaction scheme A, the reaction scheme B of Lederle Ltd.) then need through the reaction of seven steps, the present invention meets the requirement of Atom economy.In the present invention, each goes on foot reaction intermediate need be through the recrystallization purifying except that formula (XIX) compound, and other respectively goes on foot reaction product and all need not be further purified and directly drop into the next step, has shortened the production cycle greatly, has simplified operation.In addition, each step reaction solvent for use only need simply reclaim and get final product recycled, has reduced the usage quantity of solvent and to the pollution of environment, has reduced the production cost of factory.
2, raw material of the present invention is simple and easy to, low price, and each goes on foot the reaction yield height, in addition, and the Noble Metal Rhodium catalyzer that the present invention does not need applied cost to grow to even greater heights, thus production cost saved greatly.
Embodiment
The test materials that the present invention is used if no special instructions, is commercially available purchase product.Described the synthetic method of each compound in following examples respectively, the midbody compound that relates in the reaction process can pass through from initial compounds synthetic set by step, also can be directly by commercially available purchase.Although the description of the inventive method from the preparation of initial compounds, it will be understood by those skilled in the art that under the situation that a certain intermediate product can obtain technological process of the present invention can be from any one intermediate and step.
[embodiment 1] (3S, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-4-[(2R)-2-methyl isophthalic acid-propyloic]-nitrogen heterocyclic din-2-ketone (VI) synthetic
The zinc powder of 120.70g (1.857mol) is added in the anhydrous tetrahydro furan of 215ml, be heated under stirring and boil, add 177.50g (0.618mol) (3S then, 4R)-the 4-acetoxy-3-[(1R)-and the 1-tert-butyl dimethyl silica ethyl] nitrogen heterocyclic din-2-ketone (IV) and 319.50g (0.909mol) 3-(2-bromopropyl)-spiral shell [2,3-dihydro-4H-1,3-benzoxazine-2,1 '-cyclohexyl]-4-ketone (XIV) is dissolved in the mixing solutions that the anhydrous tetrahydro furan of 640ml forms, adding speed with reaction solution not bumping be advisable, adding the back refluxed 30 minutes, be cooled to room temperature, add 18g 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 215ml, add the 2N hydrochloric acid of 710ml 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-carbonyl azetidin-4-yl] propyl group }-tetrahydrofuran (THF)-toluene solution of spiral shell [2,3-dihydro-4H-1,3-benzoxazine-2,1 '-cyclohexyl]-4-ketone.This mixture enters next step without separation.
Add the tetrahydrofuran (THF) of 535ml 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 74.55g 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 460ml was 2, organic phase salt water washing 3 times.Organic phase adds 700ml 6% under 5～15 ℃ of stirrings sodium hydroxide solution adjusting pH is 10, adds the 180ml17% sodium sulfite solution 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, have mass crystallization to separate out, stirring reaction is 2 hours under uniform temp, filters, wash crystal with water, drying, obtain 150.68g (yield 81%) (3S, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-4-[(2R)-2-methyl isophthalic acid-propyloic]-nitrogen heterocyclic din-2-ketone (VI) white crystals.
Mp：146～147℃
IR
max?
neat(cm
-1)：1740，1465，1330，1255，1043，837。
1HNMR：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，br)。
[embodiment 2] (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-nitrogen heterocyclic din-2-ketone (XVI) synthetic
Under the room temperature to 90.3g (0.30mol) (3S, 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-4-[(2R)-2-methyl isophthalic acid-propyloic]-nitrogen heterocyclic din-2-ketone (VI) and 68.1g (0.33mol) two cyclohexanediamine (DCC) are dissolved in the solution of 400ml methylene dichloride and add 3g 4-Dimethylamino pyridine (DMAP), in reaction solution, drip 111.30g (0.315mol) (2S then, 4S)-and 2-dimethylamine carbonyl-4-sulfydryl-1-(to the nitro carbobenzoxy-(Cbz)) tetramethyleneimine (XV) is dissolved in the solution of 500ml methylene dichloride, and reaction is 12 hours under the room temperature.After reaction finishes, filter, collect filtrate, respectively with the acetum of 600ml 5%, saturated sodium bicarbonate solution and saturated brine washing toluene solution are respectively once, collect dichloromethane layer, add anhydrous magnesium sulfate drying, filter, the reclaim under reduced pressure methylene dichloride is in order to recycled, get 198.60g (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-nitrogen heterocyclic din-2-ketone (XVI) solid crude product (the HPLC external standard wherein contains formula (XVI) compound 171.91g, yield 90.1%), without being further purified, directly drop into the next step.
[embodiment 3] (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-nitrogen heterocyclic din-2-ketone (XVI) synthetic
Under the room temperature with (0.30mol) (3S of 100g (0.332mol), 4R)-3-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-4-[(2R)-2-methyl isophthalic acid-propyloic]-nitrogen heterocyclic din-2-ketone (VI) and 55.12g (0.349mol) N, N '-carbonyl dimidazoles (CDI) is dissolved in the 500ml acetone, in reaction solution, drip 111.69g (0.316mol) (2S then, 4S)-and 2-dimethylamine carbonyl-4-sulfydryl-1-(to the nitro carbobenzoxy-(Cbz)) tetramethyleneimine (XV) is dissolved in the solution of 600ml acetone, and reaction is 2.5 hours under the room temperature.After reaction finishes, reclaim under reduced pressure acetone is in order to recycled, surplus liquid adds the dissolving of 500ml toluene, with 700ml clear water washing toluene solution once, collect toluene layer, add anhydrous sodium sulfate drying, filter, reclaim under reduced pressure toluene is in order to recycled, get the yellow spumescence solid of 227.63g (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVI) compound 167.14g to nitrogen heterocyclic din-2-ketone (XVI) crude product, yield 87.6%), without being further purified, directly drop into the next step.
[embodiment 4] (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) synthetic
Get 32.66g and go up step reaction gained (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVI) compound 28.20g to nitrogen heterocyclic din-2-ketone (XVI) crude product, 0.044mol) be dissolved in the 250ml toluene, solution temperature is reduced to below-10 ℃, add 21.44g (0.066mol) chlorine oxalic acid to nitrobenzyl ester (XVII), in reaction solution, drip 10.65ml (0.132mol) pyridine (temperature control is in below-5 ℃ during dropping) then.After dripping off, reacted 1 hour down, slowly splash into the 300ml frozen water then in uniform temp.Drip off the back and continue to stir 10 minutes down, tell toluene layer, add saturated sodium bicarbonate solution washing three times, each 300ml in uniform temp.Collect toluene layer, add anhydrous magnesium sulfate drying, filter, reclaim under reduced pressure toluene is in order to recycled.With the gained enriched product in 50 ℃ of vacuum-dryings 3 hours; get 41.30g (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S; 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVIII) compound 35.73g to 1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) solid crude product; yield 95.6%), product is without being further purified direct input the next step.
[embodiment 5] (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl-]-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) synthetic
Getting 40.18g (0.165mol) chlorine oxalic acid is dissolved in the 100ml methylene dichloride nitrobenzyl ester (XVII), solution temperature is reduced to below-10 ℃, in solution, slowly drip 20ml (0.248mol) pyridine (temperature control is in below-5 ℃ during dropping), after dripping off, continue down to stir 15 minutes in uniform temp.On the other hand, 41.44g is gone up step reaction gained (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVI) compound 35.22g to nitrogen heterocyclic din-2-ketone (XVI) crude product, 0.055mol) be dissolved in the 300ml methylene dichloride, solution temperature is reduced to below-10 ℃, in solution, slowly add the reaction solution (temperature control in-5 ℃ below) of above-mentioned chlorine oxalic acid then nitrobenzyl ester (XVII) and pyridine.After adding, reacted 1 hour down, slowly splash into the 500ml frozen water then in uniform temp.Drip off the back and continue to stir 10 clocks down, tell toluene layer, add saturated sodium bicarbonate solution washing three times, each 500ml in uniform temp.Collect dichloromethane layer, add anhydrous magnesium sulfate drying, filter, reclaim under reduced pressure toluene is in order to recycled.With the gained enriched product in 50 ℃ of vacuum-dryings 3 hours; get 53.82g (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S; 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVIII) compound 45.21g to 1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) solid crude product; yield 97.5%), product is without being further purified direct input the next step.
[embodiment 6] (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) synthetic
Get 30.56g and go up step reaction gained (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S, 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVI) compound 24.45g to nitrogen heterocyclic din-2-ketone (XVI) crude product, 0.038mol) be dissolved in 200ml N, in the dinethylformamide (DMF), add 1.83g sodium hydride (0.076mol) below-10 ℃, after adding, continue down to stir 30 minutes in uniform temp, slowly add 18.51g (0.076mol) chlorine oxalic acid then to nitrobenzyl ester (XVII) (temperature control is in below-5 ℃), after adding, reacted 1 hour down in uniform temp, slowly splash into the 100ml frozen water then.Drip off the back and continue to stir 10 minutes down, tell toluene layer, add saturated sodium bicarbonate solution washing three times, each 200ml in uniform temp.Collect dichloromethane layer, add anhydrous magnesium sulfate drying, filter, reclaim under reduced pressure toluene is in order to recycled.With the gained enriched product in 50 ℃ of vacuum-dryings 3 hours; get 36.48g (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S; 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVIII) compound 29.95g to 1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) solid; yield 93.5%), product is without being further purified direct input the next step.
[embodiment 7] (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) synthetic
To go up step gained 35.29g (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S; 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVIII) compound 30.53g to 1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) solid; 0.036mol); 15.6ml triethyl-phosphite (0.09mol) and 1g Resorcinol catalyzer are dissolved in 120ml dimethylbenzene; be warming up to backflow under the nitrogen protection; after the insulated and stirred 5 hours; remove solvent under reduced pressure; use re-crystallizing in ethyl acetate in the surplus liquid; collect the gained solid and get (5R in 50 ℃ of vacuum-dryings; 6S; 8R; 2 ' S; 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[1-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) solid 21.93g; yield 75.1%; HPLC purity 98.3%, HPLC content 98.6%.
Compound (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-(tertiary butyl dimethyl Si base) ethyl]-the determination of physical appearance result of 4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX):
NMRδ(CD
3CN)：0.05(6H，s)，1.84(9H，s)，1.21-1.33(6H，m)，2.15-2.20(2H，m)，2.82-3.05(1H，m)，3.21-3.38(2H，m)，3.25-3.38(1H，m)，3.65-3.88(1H，m)，4.14-4.35(3H，m)，4.63-4.8l(1H，m)，5.19-5.25(4H，m)，7.42-7.70(4H，m)，8.18-8.22(4H，d)。
[α]
D?
24＝+44.49°(c＝2.5，CHCl
3)
[embodiment 8] (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) synthetic
Get step gained 14.88g (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S; 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVIII) compound 12.65g to 1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) solid; 0.015mol); add 5.2ml triethyl-phosphite (0.03mol); be warming up to 65～70 ℃ under the nitrogen protection; after the insulated and stirred 2 hours; add 40ml dimethylbenzene and 0.3g Resorcinol catalyzer; being warming up to refluxes stirred after 6 hours; remove solvent under reduced pressure in order to recycled; in surplus liquid, add the 120ml re-crystallizing in ethyl acetate; collect the gained solid and get (5R in 50 ℃ of vacuum-dryings; 6S; 8R; 2 ' S; 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[1-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) solid 8.54g; yield 70.2%; HPLC purity 97.3%; HPLC content 97.8%, the determination of physical appearance result is with embodiment 7.
[embodiment 9] (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) synthetic
Get step gained 25.40g (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si base) ethyl]-4-{ (2R)-2-methyl isophthalic acid-carbonyl ethyl-[(2S; 4R)-4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-(the HPLC external standard wherein contains formula (XVIII) compound 21.08g to 1-(to nitro benzyloxy oxalyl group)-nitrogen heterocyclic din-2-ketone (XVIII) solid; 0.025) be dissolved in 80ml toluene; add 43ml triethyl-phosphite (0.25mol); be warming up to 80～90 ℃ under the nitrogen protection; after the insulated and stirred 4 hours; remove toluene and organophosphorus under reduced pressure; add 120ml dimethylbenzene and 0.5g Resorcinol catalyzer then; being warming up to refluxes stirred after 6 hours; remove solvent under reduced pressure in order to recycled; in surplus liquid, add the 200ml re-crystallizing in ethyl acetate; collect the gained solid and get (5R in 50 ℃ of vacuum-dryings; 6S; 8R; 2 ' S; 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[1-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) solid 14.46g; yield 71.3%; HPLC purity 98.5%; HPLC content 98.1%, the determination of physical appearance result is with embodiment 7.
[embodiment 10] (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XX)
Under the room temperature, to go up step gained (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) solid 20.50g (0.025mol) is dissolved in the 110ml tetrahydrofuran (THF); and add 13ml acetic acid successively and be dissolved in the solution that 110ml tetrahydrofuran (THF) and 19.58g tetrabutyl ammonium fluoride are dissolved in the 250ml tetrahydrofuran (THF), stirred 72 hours under the room temperature.After reaction finishes, adding the 160ml saturated sodium bicarbonate aqueous solution in the ice bath downhill reaction liquid stirred 10 minutes, add the 500ml dichloromethane extraction, tell dichloromethane layer, add 300ml water washing dichloromethane solution, add anhydrous magnesium sulfate drying, concentrate and reclaim methylene dichloride, obtain yellow solid 25.65g (the HPLC external standard wherein contains formula (XX) compound 16.03g, yield 92%), product is without being further purified direct input the next step.
[embodiment 11] (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XX)
Under the room temperature, to go up step gained (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-(tertiary butyl dimethyl Si base) ethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XIX) solid 16.75g (0.021mol) is dissolved in 50ml N; in the dinethylformamide; the 7.20g ammonium bifluoride; be warming up to 40 ℃; the insulated and stirred reaction added a large amount of frozen water after 48 hours under the vigorous stirring.Then, add the 300ml ethyl acetate extraction, tell organic layer, add 100ml water washing ethyl acetate solution, add anhydrous magnesium sulfate drying, concentrate and reclaim ethyl acetate, (the HPLC external standard wherein contains formula (XX) compound 12.92g to obtain yellow solid 18.21g, yield 88.3%), product is without being further purified direct input the next step.
[embodiment 12] (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid trihydrate (I) synthetic
In the 1L autoclave, add and go up step gained (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-(the quantitative 12.5g of HPLC, 0.018mol); the 250ml tetrahydrofuran (THF); 200ml water, 5.78g 2,6-lutidine (0.054mol) and 2g palladium/carbon for 4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XX) solid 20g.The gained mixture was reacted 1 hour under the hydrogen-pressure of 1.8MPa.Remove by filter catalyzer, filtrate is under agitation used the 800ml acetone diluted.Then, drip 400ml acetone down at 5～15 ℃, drip off the back and stirred 30 minutes, filter and collect crystal, and with 50ml washing with acetone crystal, 40 ℃ of following vacuum-dryings obtain 5.74g (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-pale yellow crystals of 4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid trihydrate (I), yield 73%.
Compound (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-the determination of physical appearance result of 4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid trihydrate (I):
UV
max?H
2O?nm：297
IR
max?
KBr?cm
-1：1755，1627，1393，1252，1130
1HNMR?δ(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 13] (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid trihydrate (I) synthetic
In the 1L autoclave, add and go up step gained (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XX) solid 15g (the quantitative 9.75g of HPLC, 0.014mol), 175ml tetrahydrofuran (THF); 140ml water, 2.44g potassium hydrogen phosphate (0.014mol) and 1.56g palladium/carbon.The gained mixture was reacted 3 hours under the hydrogen-pressure of 1.8MPa.Remove by filter catalyzer, filtrate is under agitation used the 650ml acetone diluted.Then, at 5～15 ℃ of following Dropwise 35 0ml acetone, drip off the back and stirred 30 minutes, filter and collect crystal, and with 50ml washing with acetone crystal, 40 ℃ of following vacuum-dryings obtain 3.98g (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-pale yellow crystals of 4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid trihydrate (I); yield 65%, the determination of physical appearance result is with embodiment 12.
[embodiment 14] (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid trihydrate (I) synthetic
In the 1L autoclave, add and go up step gained (5R, 6S, 8R, 2 ' S, 4 ' S)-to nitrobenzyl-3-[4-(1-is to nitro carbobenzoxy-(Cbz)-2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylicesters (XX) solid 16g (the quantitative 11.35g of HPLC, 0.016mol), 200ml tetrahydrofuran (THF); 160ml water, 16.16g N-methylmorpholine (0.16mol) and 1.78g palladium/carbon.The gained mixture was reacted 1.5 hours under the hydrogen-pressure of 1.8MPa.Remove by filter catalyzer, filtrate is under agitation used the 750ml acetone diluted.Then, drip 400ml acetone down, drip off the back and stirred 30 minutes at 5～15 ℃, filter and collect crystal, and with 50ml washing with acetone crystal, 40 ℃ of following vacuum-dryings obtain 4.06g (5R, 6S, 8R, 2 ' S, 4 ' S)-3-[4-(2-dimethylin carbonyl) pyrrolidyl sulphur]-6-[(1 " R)-hydroxyethyl]-pale yellow crystals of 4-azabicyclo [3.2.0]-hept-2-ene"-7-ketone-2-carboxylic acid trihydrate (I); yield 58%, the determination of physical appearance result is with embodiment 12.
The invention is not restricted to above embodiment, all belong within the scope of the technology of the present invention and equivalent technologies thereof according to any modification of the present invention or modification.
Claims (14)
1. the preparation method of a meropenem comprises the steps:
1) make the reaction of formula (XVI) compound and formula (XVII) compound obtain formula (XVIII) compound;
2) make the reaction of formula (XVIII) compound and organophosphorus reagent generate ylide, under the effect of catalyzer phenol or Resorcinol, prepare formula (XIX) compound then;
3) make formula (XIX) compound hydrolysis obtain formula (XX) compound;
4) make formula (XX) compound reduction production (I) meropenem under catalyzer and hydrogen effect;
Reaction scheme is:
2. the described preparation method of claim 1, wherein said formula (XVI) compound is to prepare by following steps:
I) make the reaction of formula (IV) compound and formula (XIV) compound obtain formula (VI) compound;
Ii) make formula (VI) compound and formula (XV) compound reaction production (XVI) compound;
Reaction scheme is:
3. the described preparation method of claim 1, being reflected in the organic solvent of wherein said step 1) carried out under the alkali effect, the mol ratio of alkali and formula (XVII) compound is 1～2: 1, the mol ratio of formula (XVII) compound and formula (XVI) is 1.5～3: 1, described organic solvent is selected from toluene, ethyl acetate, tetrahydrofuran (THF), dioxane, methyl tert-butyl ether, methyl-phenoxide, methylene dichloride, trichloromethane, acetone, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, acetonitrile, described alkali is organic bases or mineral alkali, mineral alkali is selected from sodium hydroxide, sodium hydride, yellow soda ash, sodium bicarbonate, sodium hydrogen phosphate, potassium hydroxide, salt of wormwood, saleratus, potassium hydrogen phosphate, potassium hydride KH, organic bases is selected from pyridine, triethylamine, diisopropyl ethyl amine, the 4-Dimethylamino pyridine, 2, the 6-lutidine.
4. the described preparation method of claim 3, the mol ratio of wherein said alkali and formula (XVII) compound is 2: 1, and the mol ratio of described formula (XVII) compound and formula (XVI) compound is 1.5: 1, and described organic solvent is a toluene, and described alkali is pyridine.
5. the described preparation method of claim 1, wherein said step 2) formula (XVIII) compound generates phosphorus ylide with the organophosphorus reagent reaction earlier in inert solvent, production (XIX) compound under the effect of catalyzer then, the mol ratio of described organophosphorus reagent and formula (XVIII) compound is 2～10: 1, reaction times is 5～12 hours, described inert solvent is selected from saturated alkane, aromatic hydrocarbon, described organophosphorus reagent is selected from triphenyl phosphorus, three normal-butyl phosphorus, triethyl-phosphite, trimethyl phosphite, triisopropyl phosphite or methyl acid phosphate diethyl ester, described catalyzer are phenol or Resorcinol.
6. the described preparation method of claim 5, the mol ratio of wherein said organophosphorus reagent and formula (XVIII) compound is 2.5: 1, and described organophosphorus reagent is triethyl-phosphite or trimethyl phosphite, and inert solvent is a dimethylbenzene, and catalyzer is a Resorcinol.
7. claim 1 or 5 described preparation methods, wherein said step 2) further comprise the re-crystallization step of formula (XIX) compound.
8. the described preparation method of claim 1, the formula of wherein said step 3) (XIX) compound in organic solvent under the effect of acid, fluorochemicals or its mixture hydrolysis obtain formula (XX) compound, described organic solvent is selected from tetrahydrofuran (THF), acetone, N, dinethylformamide, methylene dichloride, ethyl acetate, N-Methyl pyrrolidone, described acid is organic acid or mineral acid, and described fluorochemicals is ammonium bifluoride or tetrabutyl ammonium fluoride.
9. the described preparation method of claim 8, wherein said formula (XIX) compound in tetrahydrofuran solvent under the effect of tetrabutyl ammonium fluoride and acetic acid hydrolysis obtain formula (XX) compound.
10. the described preparation method of claim 1, the reaction of wherein said step 4) is to carry out in the presence of alkali in organic solvent or water-containing organic solvent, described catalyzer is selected from palladium, palladium/carbon or palladium hydroxide, described alkali is mineral alkali or organic bases, and organic solvent is selected from a kind of or its arbitrary mixture in alcohols, ethers, the organic acid.
11. the described preparation method of claim 9, wherein said alkali and formula (XX) compound mol ratio is 1～10: 1.
12. the described preparation method of claim 11, the mol ratio of wherein said alkali and formula (XX) compound is 1～4: 1.
13. the described preparation method of claim 9, wherein said catalyzer is palladium/carbon.
14. the described preparation method of claim 1 comprises the steps:
1) formula (XVI) compound is dissolved in toluene, adding formula (XVII) compound and pyridine, reaction obtains formula (XVIII) compound, and the mol ratio of pyridine and formula (XVII) compound is 2: 1, and the mol ratio of formula (XVII) compound and formula (XVI) is 1.5: 1;
2) make formula (XVIII) compound be dissolved in dimethylbenzene, add Resorcinol and triethyl-phosphite or trimethyl phosphite, the back crystallization of laying equal stress on except that desolvating of reaction obtains formula (XIX) compound, and wherein the mol ratio of triethyl-phosphite or trimethyl phosphite and formula (XVIII) compound is 2.5: 1;
3) formula (XIX) compound is dissolved in the tetrahydrofuran (THF), adds tetrabutyl ammonium fluoride and acetic acid and make formula (XIX) compound hydrolysis obtain formula (XX) compound;
4) make formula (XX) compound 2, under 6-lutidine and palladium/carbon effect, under hydrogen-pressure, reduce the meropenem of production (I), wherein 2, the mol ratio of 6-lutidine and formula (XX) compound is 1～4: 1.
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| CN114133350A (en) * | 2021-12-16 | 2022-03-04 | 浙江乐普药业股份有限公司 | Preparation method of anti-neocorolla drug Paxlovid intermediate |
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| CN114133350A (en) * | 2021-12-16 | 2022-03-04 | 浙江乐普药业股份有限公司 | Preparation method of anti-neocorolla drug Paxlovid intermediate |
| CN114133350B (en) * | 2021-12-16 | 2023-05-23 | 浙江乐普药业股份有限公司 | Preparation method of anti-neocrown drug Paxlovid intermediate |
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