CN102603745A - Preparation method of beta-methyl carbapenem compound - Google Patents
Preparation method of beta-methyl carbapenem compound Download PDFInfo
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Abstract
The invention provides a preparation method of a beta-methyl carbapenem compound, which comprises the following steps of: carrying out a reaction on a compound showed in a formula (III) and a compound showed in a formula (IV) in an organic solvent for generating a compound showed in a formula (II), washing reaction products by aqueous acid, separating out an organic solution layer containing the compound showed in the formula (II), adding alkali, a catalyst and hydrogen into an organic solution containing the compound showed in the formula (II) for reacting, and crystallizing for generating a compound showed in a formula (I). According to the method, during the steps of preparing the reaction liquid containing the compound showed in the formula (II) from the compound showed in the formula (III), the washing using the aqueous acid is only carried out by one to two times, an additional post-process does not need to be carried out, and then a next reaction step can be carried out.
Description
Technical field
The present invention relates to a kind of preparation method of beta-methyl carbon penicillenic compound; Specifically; Relate to (4R; 5S, 6S)-3-[[(3S, 5S)-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-preparation method of 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid trihydrate.
Background technology
Compound shown in the general formula (I); I.e. (4R; 5S; 6S)-3-[[(3S, 5S)-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid trihydrate is the important source material of production of antibiotics in the pharmaceutical industry.Chinese invention patent application CN101410398A discloses the preparation method of compound shown in the formula (I): in the presence of alkali, and the reaction of compound shown in compound shown in the formula (III) and the formula (IV), compound shown in the synthesis type (II).
The reaction solution that will contain compound shown in the formula (II) extracts/salt solution washing/water washing, obtains containing the water saturation ethyl acetate solution of compound shown in the formula (II).In the water saturation ethyl acetate solution that contains compound shown in the formula (II), add palladium-carbon catalyst; Carry out the hydrogenation deprotection reaction; React the after-filtration that finishes and remove palladium carbon, the reaction solution that will contain compound shown in the formula (I) is with acid for adjusting pH/concentrating under reduced pressure/adding gac stirring/filtration/adding solvent crystallization.In above-mentioned preparation method, a series of last handling processes such as the reaction solution of compound shown in the midbody formula (II) need extract, salt solution washing, water washing; The reaction solution that contains compound shown in the formula (I) that obtains need be used a series of last handling processes such as acid for adjusting pH, concentrating under reduced pressure, the stirring of adding gac and filtration equally; Cause this preparing method's complex steps, cost increase, material loss to increase and increasing environmental pollution, be unfavorable for the suitability for industrialized production of pharmaceutical industry and the environmental requirement of pay attention to day by day.
Summary of the invention
Therefore, but the objective of the invention is to seek that a kind of operation is succinct, method that environmental protection and heavy industrialization prepare compound shown in the formula (I).
Be used to realize that the technical scheme of above-mentioned purpose is following:
The preparation method of compound shown in a kind of formula (I), this preparation method may further comprise the steps:
(A) compound shown in compound shown in the formula (III) and the formula (IV) is reacted compound shown in the production (II) in the presence of alkali in organic solvent, use aqueous acid washing reaction product and isolate the organic solution layer that contains compound shown in the formula (II);
(B) in the organic solution that contains compound shown in the formula (II), add alkali, catalyzer and hydrogen and react compound shown in the post crystallization production (I).
Wherein, R
1Be acyl group.
R specifically
1Can be for not replacing or substituted carbonic acyl radical, alkylsulfonyl or phosphoryl;
Preferably, the substituting group of substituted carbonic acyl radical, alkylsulfonyl or phosphoryl be aliphatic group, alicyclic hydrocarbon radical, aromatic base, heterocyclic radical, amino, fatty-oxyl, fragrant oxygen base, by aromatic base or the substituted aliphatic group of heterocyclic radical or by aromatic base or the substituted amino of heterocyclic radical;
Further preferably, said R
1Be selected from alkyloyl, for example formyl radical, ethanoyl, propionyl group, butyryl radicals, pentanoyl and caproyl with 1 to 6 carbon atom; Acryl; Alkyl sulphonyl with 1 to 6 carbon atom, for example methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl and own alkylsulfonyl; Alkoxy acyl with 1 to 5 carbon atom, for example methoxy acyl group, ethoxy acyl group, the third oxygen acyl group, fourth oxygen acyl group and penta kind of acyl group; The propenyloxy group carbonyl; Alcoxyl phosphoryl with 1 to 5 carbon atom, for example diethoxy phosphoryl; Benzoyl group; Benzenesulfonyl, for example p-toluenesulfonyl; The benzene phosphoryl; Benzene oxygen phosphoryl, for example hexichol oxygen phosphoryl; The phenyl amino acyl group, N-phenyl amino formyl radical; Furancarbonyl; The thiazolyl carbonyl; Phenyl acetyl; The phenyl propionyl group; Carbobenzoxy-(Cbz); The imidazolyl ethanoyl;
More preferably, R
1Be two aryloxy phosphoryls;
Most preferably, R
1Be two phenoxy phosphoryls.
In said step (A), said alkali can be organic bases, trialkylamine for example, Trimethylamine, triethylamine, Tributylamine, triamylamine, trihexylamine, trioctylamine and N, N-diisopropyl ethyl amine; Dialkylamine, N, N-diisopropylamine; Pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Quinoline; The N-alkyl morpholine; And in the tetramethyl guanidine one or more, be preferably N, N-diisopropyl ethyl amine, N, N-diisopropylamine or tetramethyl guanidine;
Said organic solvent is selected from: N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; One or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene;
Said aqueous acid is selected from mineral acid, for example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, potassium primary phosphate and SODIUM PHOSPHATE, MONOBASIC; Organic acid, the for example aqueous solution of one or more in formic acid, acetate, sulfonic acid and the trifluoroacetic acid.The preferably phosphoric acid sodium dihydrogen.
In said step (A), the mol ratio of said formula (IV) compound and formula (III) compound is 1: 0.8～3.0, is preferably 1: 1.0～1.5 moles; The mol ratio of compound is 1: 0.8～5.0 moles shown in said alkali and the formula (III), is preferably 1: 1.0～3.0 moles; The temperature of said reaction is-50 ℃～50 ℃, is preferably-30 ℃～30 ℃; The mass ratio of compound is 1～40: 1 shown in said organic solvent and the said formula (III), is preferably 2～20: 1; The volume ratio of said aqueous acid and reaction product is 1: 0.1～20, be preferably 1: 0.5～and 10; The concentration of said aqueous acid is 0.01 mol～10 mol, is preferably 0.01 mol～5 mol; The temperature of said washing is 0 ℃～40 ℃, is preferably 20 ℃～40 ℃, more preferably 34 ℃.
In said step (A), when isolating the organic solution layer that contains compound shown in the formula (II), add and the immiscible organic solvent of water, be preferably halohydrocarbon, for example methylene dichloride and trichloromethane; Ester, for example ETHYLE ACETATE and methyl acetate; Hydrocarbon, for example sherwood oil and Skellysolve A; Aromatic hydrocarbon, for example toluene; Alcohol, for example propyl carbinol and Pentyl alcohol; Ketone, for example 2-butanone and 2 pentanone; Ether, for example one or more in the ether.
In said step (B), the organic solution that will contain compound shown in the formula (II) before the reaction is concentrated, reacts perhaps that organic solution that forward direction contains compound shown in the formula (II) adds entry and/or one or more are selected from N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; Methyl alcohol, ethanol, n-propyl alcohol and Virahol; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, the organic solvent of one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene.
In said step (B), said alkali is selected from organic bases, for example pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Morpholine; Quinoline; Pyrimidine; The 4-Dimethylamino pyridine; Triethylamine, diethylamine, Tributylamine, diisopropylethylamine and diisopropylamine; Mineral alkali, for example Sodium phosphate, dibasic, potassium hydrogenphosphate; In yellow soda ash and the salt of wormwood one or more; Said catalyzer is the catalyzer that contains palladium and/or platinum, is preferably the catalyzer that contains palladium, more preferably is carried on the palladium catalyst on the gac; Said crystalline solvent is selected from nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol, one or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example are preferably in methylene dichloride, THF, acetonitrile, acetone and the methyl alcohol one or more.
In said step (B), the pressure of hydrogen is 0.05～6.0MPa, is preferably 0.1～4.0MPa; The temperature of said reaction is 0～70 ℃, is preferably 15～50 ℃; The volume ratio of said crystalline solvent and reaction product is 0.2～50: 1, is preferably 1～10: 1.
In said step (B), add crystal seed during said crystallization; Stir in the said crystallisation process or do not stir.
The inventor is through discover in a large number; The reaction solution that contains compound shown in the formula (II) that the reaction of compound shown in compound shown in the formula (III) and the formula (IV) obtains only need be used acidiferous solution washing one to ten time; Be preferably five times; Need not to carry out other aftertreatment and promptly can be used for next step reaction, otherwise can have influence on the subsequent reactions product, be i.e. the quality product and the yield of compound shown in the formula (I).And the reaction solution that contains compound shown in the formula (II) that will pass through this kind processing concentrates; Add entry, organic solvent, alkali, noble metal catalyst; In autoclave, feed the reaction solution that the hydrogen deprotection obtains containing compound shown in the formula (I), remove by filter catalyzer, the reaction solution of this moment need not to carry out other aftertreatment; Directly add the recrystallisation solvent crystallization, promptly can obtain compound shown in good, the high-quality formula of yield (I).
Embodiment
Below in conjunction with embodiment the present invention is further described in detail, the embodiment that provides has been merely and has illustrated the present invention, rather than in order to limit scope of the present invention.
Embodiment 1
Initial compounds IIIa prepares according to Chinese patent ZL200610057578.6 disclosed method.If no special instructions, other test materials is commercially available.
Compound (4R; 5S; 6S)-3-[[(3S, 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid is to the preparation of nitrobenzyl ester (II)
Compound (4R with 33.0g; 5R; 6S)-3-two phenoxy phosphorus acyloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid joins in the reaction flask nitrobenzyl ester (IIIa); Add 200.0g acetonitrile, 10.0g diisopropylethylamine, compound shown in the 19.0g formula IV is-10 ℃ of reactions down.Reaction finishes, and in reaction solution, adds 500g ETHYLE ACETATE, and with 6% (g/mL) SODIUM PHOSPHATE, MONOBASIC solution washing twice of 500 milliliters, wash temperature is 34 ℃, and phase-splitting obtains containing the organic solution of compound shown in the formula II.
Embodiment 2
(4R, 5S, 6S)-3-[[(3S, 5S)-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-preparation of 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid trihydrate (I)
With obtain among the embodiment 1 contain compound (II) (promptly (and 4R, 5S, 6S)-3-[[(3S; 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid is to the nitrobenzyl ester) organic solution concentrate, liquid concentrator imports in the autoclave, adds the THF of 600g; The lutidine that adds the palladium-carbon catalyst 3.5g of 20g imports hydrogen, and pressure is to the 0.5MPa; Temperature is controlled at 0～50 ℃ of reaction; Reaction finishes, and removes by filter catalyzer such as palladium carbon, and filtrating is transferred in the crystallization bottle; The acetone that adds 1000g is in 0 ℃ of left and right sides stirred crystallization.Filter, obtain the compound (I) of 18.2g.
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
Present embodiment is used for research and from the aftertreatment of the reaction solution of compound shown in the compound formula (II) shown in the formula (III), adopts the influence of different treatment method to preparation feedback.
Adopt with embodiment 1 to prepare compound shown in the formula (I) with embodiment 2 similar methods, different is in compound aftertreatment shown in the midbody formula (II), to adopt following two kinds of methods to handle respectively:
Method is 1.: use washing once, use the salt solution washed twice, use washing once then;
Method is 2.: use potassium primary phosphate (KH
2PO
4) solution washing five times.
Obtain following result according to above-mentioned two kinds of treatment processs:
(1) 1. method of use is handled, and occurs being prone to emulsification in the treating processes, and phase-splitting is difficult, needs the long period phase-splitting; 2. method of use then is prone to phase-splitting, and processing reaction speed is fast;
See from the liquid phase collection of illustrative plates that (2) after aftertreatment, 1. method of use is handled, have little impurity peaks to become big phenomenon, promptly impurity obviously increases, and causes serious adverse drug reaction easily; 2. method of use is handled does not then have this phenomenon;
(3) 1. 2. to handle the product productive rate that obtains obviously different with method for method of use.
Adopt with embodiment 1 and prepare compound shown in the formula (I) with embodiment 2 similar methods; Different is in compound aftertreatment shown in the midbody formula (II), to adopt method 1. 2. to handle with method respectively; 1. two batches of experiments have been carried out according to method; 2. carry out a collection of experiment according to method and compared result such as table 1.
Table 1 different treatment method is to the influence of product productive rate
Can find out that from table 1 2. method of use handle, the product productive rate that obtains is obviously higher.
Conclusion: shown in the formula (III) shown in the compound formula (II) in the reaction solution of compound method of use 2. can so that to the organic solution system that contains compound shown in the formula (II) purer; Thereby make shown in the formula (II) shown in the compound formula (I) that reaction system can obtain product through direct crystallization in the compound after reacting completely, and purity and yield are higher; And if in that method of use is 2. in the reaction solution of compound shown in the compound formula (II) shown in the formula (III); Instant brine wash; On the one hand, occur emulsion in the last handling process easily, can cause the reduction on compound yield losses shown in the product solution Chinese style (II) and the purity; On the other hand; If shown in the formula (II) shown in the compound formula (I) in the compound according to direct crystallization method of the present invention; The product purity of compound shown in the formula that obtains (I) can be influenced; Thereby must adopt loaded down with trivial details post-treating method to obtain the purity high product, its yield reduces greatly.
Embodiment 4
Present embodiment is used for studying and is adopting the influence of different types of washing soln to product output and yield shown in the formula (III) shown in the compound formula (II) in the aftertreatment of the reaction solution of compound.
Adopt with embodiment 1 to prepare compound shown in the formula (I) with embodiment 2 similar methods, different is in compound aftertreatment shown in the midbody formula (II) respectively the solution shown in the employing table 2 wash, the result is as shown in table 2.
The different types of washing soln of table 2 is to the influence of product output and yield
Can know by last table 2,, select washing soln very crucial shown in the formula (III) shown in the compound formula (II) in the aftertreatment of the reaction solution of compound; Different washing solns is very big to the purity and the yield influence of the finished product; Use acidic aqueous solution, for example the aqueous solution of SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate is compared with other kinds solution; Can improve the purity and the yield of compound bullion output shown in the formula (I) greatly so that the organic solution system of compound is purer shown in the formula that arrives (II).It can also be seen that by table 2 aqueous solution that uses potassium primary phosphate is as the washing soln better effects if.
Embodiment 5
Present embodiment is used for studying and is adopting the influence of different wash temperatures to product output shown in the formula (III) shown in the compound formula (II) in the aftertreatment of the reaction solution of compound.
Adopt with embodiment 1 similar method to prepare compound shown in the formula (II), different is in aftertreatment respectively the wash temperature shown in the employing table 3 wash, the result is as shown in table 3.
The different wash temperatures of table 3 are to the influence of product output
Can know by table 3; Compound shown in compound shown in the formula (III) and the formula (IV) is being reacted in organic solvent in the presence of alkali in the reaction solution of compound shown in the production (II), and use aqueous acid washing reaction product is also isolated in the organic solution layer that contains compound shown in the formula (II), and wash temperature has very big influence to the output of compound shown in the formula (II); Consider ultimate capacity; Wash temperature can be 0 ℃～40 ℃, is preferably 20 ℃～40 ℃, and the best is 34 ℃.
Claims (9)
1. the preparation method of compound shown in the formula (I), this preparation method may further comprise the steps:
(A) compound shown in compound shown in the formula (III) and the formula (IV) is reacted compound shown in the production (II) in the presence of alkali in organic solvent, use aqueous acid washing reaction product and isolate the organic solution layer that contains compound shown in the formula (II);
(B) in the organic solution that contains compound shown in the formula (II), add alkali, catalyzer and hydrogen and react compound shown in the post crystallization production (I).
Wherein, R
1Be acyl group.
2. preparation method according to claim 1 is characterized in that, said R
1For not replacing or substituted carbonic acyl radical, alkylsulfonyl or phosphoryl;
Preferably, the substituting group of substituted carbonic acyl radical, alkylsulfonyl or phosphoryl be aliphatic group, alicyclic hydrocarbon radical, aromatic base, heterocyclic radical, amino, fatty-oxyl, fragrant oxygen base, by aromatic base or the substituted aliphatic group of heterocyclic radical or by aromatic base or the substituted amino of heterocyclic radical;
Further preferably, said R
1Be selected from alkyloyl, for example formyl radical, ethanoyl, propionyl group, butyryl radicals, pentanoyl and caproyl with 1 to 6 carbon atom; Acryl; Alkyl sulphonyl with 1 to 6 carbon atom, for example methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl and own alkylsulfonyl; Alkoxy acyl with 1 to 5 carbon atom, for example methoxy acyl group, ethoxy acyl group, the third oxygen acyl group, fourth oxygen acyl group and penta kind of acyl group; The propenyloxy group carbonyl; Alcoxyl phosphoryl with 1 to 5 carbon atom, for example diethoxy phosphoryl; Benzoyl group; Benzenesulfonyl, for example p-toluenesulfonyl; The benzene phosphoryl; Benzene oxygen phosphoryl, for example hexichol oxygen phosphoryl; The phenyl amino acyl group, N-phenyl amino formyl radical; Furancarbonyl; The thiazolyl carbonyl; Phenyl acetyl; The phenyl propionyl group; Carbobenzoxy-(Cbz); The imidazolyl ethanoyl;
More preferably, R
1Be two aryloxy phosphoryls;
Most preferably, R
1Be two phenoxy phosphoryls.
3. preparation method according to claim 1 and 2 is characterized in that, in said step (A), said alkali is organic bases, trialkylamine for example, Trimethylamine, triethylamine, Tributylamine, triamylamine, trihexylamine, trioctylamine and N, N-diisopropyl ethyl amine; Dialkylamine, N, N-diisopropylamine; Pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Quinoline; The N-alkyl morpholine; And in the tetramethyl guanidine one or more, be preferably N, N-diisopropyl ethyl amine, N, N-diisopropylamine or tetramethyl guanidine;
Said organic solvent is selected from: N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; One or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene;
Said aqueous acid is selected from mineral acid, for example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, potassium primary phosphate and SODIUM PHOSPHATE, MONOBASIC; Organic acid, the for example aqueous solution of one or more in formic acid, acetate, sulfonic acid and the trifluoroacetic acid; Be preferably potassium primary phosphate or SODIUM PHOSPHATE, MONOBASIC.
4. according to each described preparation method in the claim 1 to 3, it is characterized in that in said step (A), the mol ratio of said formula (IV) compound and formula (III) compound is 1: 0.8～3.0, is preferably 1: 1.0～1.5 moles; The mol ratio of compound is 1: 0.8～5.0 moles shown in said alkali and the formula (III), is preferably 1: 1.0～3.0 moles; The temperature of said reaction is-50 ℃～50 ℃, is preferably-30 ℃～30 ℃; The mass ratio of compound is 1～40: 1 shown in said organic solvent and the said formula (III), is preferably 2～20: 1; The volume ratio of said aqueous acid and reaction product is 1: 0.1～20, be preferably 1: 0.5～and 10; The concentration of said aqueous acid is 0.01 mol～10 mol, is preferably 0.01 mol～5 mol; The temperature of said washing is 0 ℃～40 ℃, is preferably 20 ℃～40 ℃, more preferably 34 ℃.
5. according to each described preparation method in the claim 1 to 4; It is characterized in that, in said step (A), when isolating the organic solution layer that contains compound shown in the formula (II), add and the immiscible organic solvent of water; Be preferably halohydrocarbon, for example methylene dichloride and trichloromethane; Ester, for example ETHYLE ACETATE and methyl acetate; Hydrocarbon, for example sherwood oil and Skellysolve A; Aromatic hydrocarbon, for example toluene; Alcohol, for example propyl carbinol and Pentyl alcohol; Ketone, for example 2-butanone and 2 pentanone; Ether, for example one or more in the ether.
6. according to each described preparation method in the claim 1 to 5; It is characterized in that; In said step (B); The organic solution that will contain compound shown in the formula (II) before the reaction is concentrated, reacts perhaps that organic solution that forward direction contains compound shown in the formula (II) adds entry and/or one or more are selected from N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; Methyl alcohol, ethanol, n-propyl alcohol and Virahol; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, the organic solvent of one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene.
7. according to each described preparation method in the claim 1 to 6, it is characterized in that in said step (B), said alkali is selected from organic bases, for example pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Morpholine; Quinoline; Pyrimidine; The 4-Dimethylamino pyridine; Triethylamine, diethylamine, Tributylamine, diisopropylethylamine and diisopropylamine; Mineral alkali, for example Sodium phosphate, dibasic, potassium hydrogenphosphate; In yellow soda ash and the salt of wormwood one or more; Said catalyzer is the catalyzer that contains palladium and/or platinum, is preferably the catalyzer that contains palladium, more preferably is carried on the palladium catalyst on the gac; Said crystalline solvent is selected from nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol, one or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example are preferably in methylene dichloride, THF, acetonitrile, acetone and the methyl alcohol one or more.
8. according to each described preparation method in the claim 1 to 7, it is characterized in that in said step (B), the pressure of hydrogen is 0.05～6.0MPa, is preferably 0.1～4.0MPa; The temperature of said reaction is 0～70 ℃, is preferably 15～50 ℃; The volume ratio of said crystalline solvent and reaction product is 0.2～50: 1, is preferably 1～10: 1.
9. according to each described preparation method in the claim 1 to 8, it is characterized in that, in said step (B), add crystal seed during said crystallization; Stir in the said crystallisation process or do not stir.
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| PCT/CN2011/000076 WO2012097471A1 (en) | 2011-01-18 | 2011-01-18 | PREPARATION METHOD OF β-METHYL CARBAPENEM COMPOUND |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101410398A (en) * | 2006-03-28 | 2009-04-15 | 株式会社钟化 | Improved process for producing carbapenem compound |
| CN101348486A (en) * | 2008-08-29 | 2009-01-21 | 深圳市海滨制药有限公司 | Preparation of meropenem |
| CN101914098A (en) * | 2010-07-20 | 2010-12-15 | 深圳市海滨制药有限公司 | Preparation method of Meropenem trihydrate crystals |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
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