CN101665499A - Manufacturing process for cephem compounds - Google Patents
Manufacturing process for cephem compounds Download PDFInfo
- Publication number
- CN101665499A CN101665499A CN200910118653A CN200910118653A CN101665499A CN 101665499 A CN101665499 A CN 101665499A CN 200910118653 A CN200910118653 A CN 200910118653A CN 200910118653 A CN200910118653 A CN 200910118653A CN 101665499 A CN101665499 A CN 101665499A
- Authority
- CN
- China
- Prior art keywords
- reaction
- aforementioned
- formula
- solution
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a manufacturing process for cephem compounds. In the mixture solvent mixed with a volume ratio between hydrochloric ether and lower alcohol (the former : the latter) between 10:1, the compound of 3-[(triphenylphosphine) methyl]-3-cephem represented by the general formula (I) is reacted with 4-methylthiazol-5-formol within a temperature range between +5 DEG C. and -50 DEG C.to obtain a compound of 3-[2-(4-methylthiazol-5-)ethenyl]-3-cephem (A) represented by the general formula (A). In the chemical formula, R[1] and R[2] represent aromatic alkyl group.
Description
Technical field
The present invention relates to the manufacture method of cephem compounds.In more detail, the present invention relates to selectivity and make method with high yield as the Z body (cis-isomeride) of the useful cephem compounds of the synthetic intermediate of cephalosporins.
Background technology
As one of cephalosporins, 3-(2-(4-methylthiazol-5-yl)-vinyl)-cephalosporin compound is arranged.Existence is for two keys of 3 vinyl in this compound, and cephem ring and 4-methylthiazol-5-base are with the complex bound Z body of cis (cis-isomeride) with trans complex bound E body (trans-isomer(ide)).In the middle of these isomer, compare with the E body, antibiotic each excellent of Z body, therefore, the optionally synthetic Z body of expectation.
The method of the Z isomer of optionally making 3-(2-replacement-vinyl)-cynnematin is disclosed in the following patent documentation 1.This manufacture method is: 7-N-is not replaced or replace-amino-3-[(three replacement-Ya phosphoranyls (phosphoranylidene)) methyl]-3-cephem-4-carboxylic acid or its ester and 4-replaces or not replacement-thiazole-5-formaldehyde in solvent and under specific temperature conditions, react.As this solvent, the solvent that uses chlorinated hydrocarbon solvent and low-grade alkane alcohol to mix with 1: 3～0.25 ratio (capacity benchmark).
Patent documentation 1: the international brochure that discloses No. 1998/058932
Summary of the invention
The problem that invention will solve
But even if according to the manufacture method of putting down in writing in the patent documentation 1, the yield of Z body can not be said so fully.
Therefore, the objective of the invention is to, selectivity is provided and makes method with high yield as the Z body of the useful cephem compounds of the synthetic intermediate of cephalosporins.
The method of dealing with problems
The inventor etc. have carried out deep research, found that, at the 3-[(triphenylphosphine) methyl]-3-cephem (3-[(triphenylphosphoranylidene) methyl]-3-cephem) in the reaction of compound and 4-methylthiazol-5-formaldehyde, use the mixed solvent of hydrochloric ether and lower alcohol as reaction solvent, the blending ratio that makes the solvent in this mixed solvent is at specified range, further temperature condition also is controlled at specified range and reacts, thereby can realize aforementioned purpose.
The present invention is based on aforementioned opinion and finishes, it provides a kind of manufacture method of cephem compounds, it is characterized in that, hydrochloric ether and lower alcohol with the volume ratio below 10: 1 (the former: in the mixed solvent that the latter) mixes, make the 3-[(triphenylphosphine shown in the following general formula (I)) methyl]-the 4-methylthiazol-5-formaldehyde shown in 3-cephem compounds and the following formula (II) is+5 ℃～-50 ℃ reactions down, obtains the 3-[2-shown in the following general formula (A) (4-methylthiazol-5-yl) vinyl]-the 3-cephem compounds.
(in the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl.)
(in the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl.)
Embodiment
Below, the present invention is described in detail based on the preferred embodiment of the present invention.In the manufacture method of the present invention, hydrochloric ether and lower alcohol with the volume ratio below 10: 1 (the former: in the mixed solvent that the latter) mixes, make the 3-[(triphenylphosphine shown in the aforementioned formula (I)) methyl]-the 3-cephem compounds (below, also be called phosphorane (Phosphorane) compound shown in the aforementioned formula (I)) with aforementioned formula (II) shown in 4-methylthiazol-5-formaldehyde+5 ℃～-50 ℃ reactions, obtain the 3-[2-shown in the aforementioned formula (A) (4-methylthiazol-5-yl) vinyl]-the 3-cephem compounds (below, also be called the cephem compounds shown in the aforementioned formula (A)).By this method, alternative compared with the past and make the Z body of cephem compounds with high yield.
In the aforementioned formula (I), R
1And R
2Expression replaces or unsubstituted aromatic hydrocarbyl.Aromatic hydrocarbyl comprises aryl and aralkyl.As aryl, can enumerate phenyl, p-methylphenyl etc.As aralkyl, can enumerate benzyl, to methoxy-benzyl etc.R
1And R
2Can be the same or different.
The reactive ratio of the 4-methylthiazol-5-formaldehyde shown in positive phosphine compound shown in the aforementioned formula (I) and the aforementioned formula (II) is: with respect to 1 mole the former, the latter is 1～15 mole, is preferably 5～10 moles especially.
4-methylthiazol-5-formaldehyde shown in the aforementioned formula (II) can be by for example obtaining commercially available 2-(4-methyl-5-thiazole) ethylhexoate (can change into reagent etc. from Tokyo has bought) hydrolysis rear oxidation.This hydrolysis and oxidation can be undertaken by ordinary method.In addition, the 4-methylthiazol-5-formaldehyde shown in the aforementioned formula (II) also can obtain with reference to the method for putting down in writing in the TOHKEMY 2006-76897 communique.
As solvent, use the mixed solvent of hydrochloric ether and lower alcohol.Both mixture ratios (the former: the latter) count below 10: 1 with volume reference, be preferably 10: 0.2～1, more preferably 10: 0.5～1.By using such mixed solvent, the yield of the cephem compounds shown in the aforementioned formula (A) improves all the more.With respect to positive phosphine compound 100 weight parts shown in the aforementioned formula (I), the consumption of mixed solvent is preferably 800～3000 weight parts.
As aforementioned hydrochloric ether, can enumerate monochloro methane, methylene dichloride, trichloromethane (chloroform), monochlorethane, ethylene dichloride, trichloroethane etc.These hydrochloric ethers can use more than 2 kinds alone or in combination.In the middle of these, preferred chloroform, methylene dichloride.
The preferred carbon number of aforementioned lower alcohol is 1～5, is preferably 2 or 3 especially.As aforementioned lower alcohol, can enumerate methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol, ethylene glycol, ethylene glycol monomethyl ether, 1,2-propylene glycol, 1, ammediol, neopentyl glycol, 1,2-butyleneglycol, 1,3 butylene glycol, 1,4-butyleneglycol etc.These lower alcohols can use more than 2 kinds alone or in combination.Among the present invention, when especially using glycols as lower alcohol, further selectivity and make the Z body of cephem compounds with high yield is preferred in this respect.So-called glycols among the present invention except comprising the common diol compound with 2 OH bases, also comprises the monoether (for example ethylene glycol monomethyl ether) and the monoesters (for example monoesters of ethylene glycol and acetate) of diol compound.
Temperature of reaction is+5 ℃～-50 ℃ as described above like that.According to the composition and the amount of employed mixed solvent, from the suitable selective reaction temperature of this temperature range.Temperature of reaction preferably from 0 ℃～-50 ℃, more preferably from-10 ℃～-30 ℃ selections.By under the temperature of this scope, reacting, can reduce output, the selectivity of E body and obtain the Z body with high yield.
Reaction times is not particularly limited, and disappears as long as reaction proceeds to the positive phosphine compound shown in the aforementioned formula (I) that can confirm to join reaction system.Also depend on composition and amount, the temperature of reaction etc. of employed mixed solvent, use 4～24 hours usually, the positive phosphine compound shown in the aforementioned formula (I) disappears, and reaction finishes.
Reaction also can be carried out aftertreatment after finishing as required.For example, in the gained reaction solution, add the potassium pyrosulfite solution washing, can remove the 4-methylthiazol-5-formaldehyde shown in the residual aforementioned formula (II).In addition, under 4-methylthiazol-5-formaldehyde shown in the aforementioned formula (II) and the situation as reaction of the amino in the cephem compounds shown in the aforementioned formula (A) of target compound and formation schiff base, the ethanolic soln that preferably adds girard reagent (Girard ' s reagent) is to decompose schiff base.
In the manufacture method of cephem compounds of the present invention, as required, can after reaction finishes, for example as following, operate, separate desired Z body, be the cephem compounds shown in the aforementioned formula (A) from the reaction solution that carries out aforementioned aftertreatment.Behind sodium chloride aqueous solution washing reaction liquid, evaporating solvent under reduced pressure or under the normal pressure, concentrate.In the concentrated solution of gained or solid residue, add methyl alcohol, vinyl acetic monomer or N-BUTYL ACETATE and when placing, Z body crystallization and separating out.The Z body purity height of gained, other purification that need not to be used to remove the E body.
Among the present invention, as the positive phosphine compound shown in the aforementioned formula (I), use when carrying out material that following operation 1～3 obtains successively, further selectivity and make the Z body of cephem compounds with high yield is preferred in this respect.
At first, operation 1 is described.In this operation, make the chlorination aza cyclo-butanone derivatives shown in the following general formula (1) (below, also only be called the chlorination aza cyclo-butanone derivatives) below pH8, react in the solvent that comprises alcohol with alkoxide, obtain the crystal of the 3-chloromethyl-3-Cephem Derivative shown in the following general formula (2).
(in the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl.R
3Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue.)
(in the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl.)
Previous reaction can be added drop-wise in the solution (C) that contains alcohol with the solution (B) that contains alkoxide by the solution (A) that will contain aforementioned chlorination aza cyclo-butanone derivatives carries out.The dripping quantity of solution (A) and solution (B) is: with respect to 1 mole of chlorination aza cyclo-butanone derivatives contained in the solution (A), alkoxide contained in the preferred solution (B) satisfies 0.8～1.5 mole ratio.In addition, the content of contained alcohol is 30～95 weight % in the preferred reaction solvent that drips after making dropping finish.
In addition, previous reaction is preferably as follows carries out: at first, to contain the amount that is equivalent to normal 5～30 moles of % of reaction of chlorination aza cyclo-butanone derivatives in the middle of total usage quantity of solution (A) of aforementioned chlorination aza cyclo-butanone derivatives, be added drop-wise in the aforementioned solution (C) that contains alcohol, then, rest solution (A) and the solution (B) that contains alkoxide are added drop-wise in the solution (C) simultaneously.
Below, solution (A)～(C) and reaction conditions are illustrated in greater detail.
The solution (A) that contains the chlorination aza cyclo-butanone derivatives
Represent the R in the aforementioned formula (1) of aforementioned chlorination aza cyclo-butanone derivatives
1And R
2With the R in the aforementioned formula (I)
1And R
2Define identically, expression replaces or unsubstituted aromatic hydrocarbyl.Aromatic hydrocarbyl comprises aryl and aralkyl.As aryl, can enumerate phenyl, p-methylphenyl etc.As aralkyl, can enumerate benzyl, to methoxy-benzyl etc.R
1And R
2Can be the same or different.
In the aforementioned formula (1) of the aforementioned chlorination aza cyclo-butanone derivatives of expression, R
3Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue.As replacing or unsubstituted aryl, specifically, can enumerate phenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, rubigan, five chlorophenyl etc.In addition, as replacing or unsubstituted heterocycle residue, can enumerate 2-pyridyl, 2-[4-morpholinodithio base, 1,3,4-thiadiazoles-5-base, 2-methyl isophthalic acid, 3,4-thiadiazoles-5-base, 1,2,3,4-tetrazolium-5-base, 1-methyl isophthalic acid, 2,3,4-tetrazolium-5-base, 1-phenyl-1,2,3,4-tetrazolium-5-base etc.
About aforementioned chlorination aza cyclo-butanone derivatives, the R in the general formula (1) for example
1Be benzyl, R
2Be compound, can synthesize by the method for putting down in writing among the JP5-9425B to methoxy-benzyl.About the chlorination aza cyclo-butanone derivatives beyond this, also can be synthetic based on the method for putting down in writing among the JP5-9425B.
In solution (A),, for example can enumerate ester classes such as methyl-formiate, ethyl formate, ritalin, vinyl acetic monomer, N-BUTYL ACETATE, ethyl propionate as the solvent of the aforementioned chlorination aza cyclo-butanone derivatives of dissolving; Halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, ethylene dibromide, chlorobenzene; Ethers such as diethyl ether, dibutyl ether, diox, tetrahydrofuran (THF); Nitrile such as acetonitrile, butyronitrile; Hydro carbons such as pentane, hexane, hexanaphthene etc.These solvents can use a kind or use more than 2 kinds (below, be called " A1 solvent ".)。In the middle of these, preferably use ethers, particularly diox.
In the aforementioned solution (A), with respect to aforementioned chlorination aza cyclo-butanone derivatives 100 weight parts, the content of aforementioned A1 solvent is preferably 50～500 weight parts, 100～500 weight parts more preferably.
But the solution former state that is dissolved with aforementioned chlorination aza cyclo-butanone derivatives in the aforementioned A1 solvent is used as solution (A), but the viscosity height of this solution.For example, use is dissolved in diox with aforementioned chlorination aza cyclo-butanone derivatives and obtains the De dioxane solution, because the fusing point of diox is 11 ℃ during as the preferred above-mentioned diox of A1 solvent, thereby when being made as temperature of reaction for example below 10 ℃, viscosity rises or solidifies.In order to prevent this phenomenon, in the solution that the aforementioned chlorination aza cyclo-butanone derivatives of dissolving forms in aforementioned A1 solvent, further add dissolving chlorination aza cyclo-butanone derivatives alcohol (below, be called " A2 solvent ".) when using, the operability transfiguration when viscosity reduction and dropping is easy, so preferred.
As aforementioned alcohol (A2 solvent), for example can enumerate lower alcohols such as methyl alcohol, ethanol, Virahol, n-propyl alcohol.These lower alcohols can use a kind or make up more than 2 kinds and to use.In the middle of these, when using methyl alcohol or ethanol under reaction conditions described later, to react, can high yield and high purity obtain the crystal of the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2), so preferably.
In the solution (A), with respect to aforementioned chlorination aza cyclo-butanone derivatives 100 weight parts, the content of aforementioned alcohol (A2 solvent) is preferably 100～500 weight parts, the scope of 200～300 weight parts more preferably.
The content of the aforementioned chlorination aza cyclo-butanone derivatives in the solution (A) is preferably 0.05～1 mole/L, 0.1～0.5 mole/L more preferably.
The solution (B) that contains alkoxide
Aforementioned alkoxide is with general formula R
4-OM represents.R in this general formula
4A straight chain shape or a catenate low alkyl group for carbon number 1-4.For example can enumerate alkyl such as methyl, ethyl, sec.-propyl, n-propyl.M in this general formula represents basic metal such as lithium, sodium, potassium.
As the concrete compound of aforementioned alkoxide, for example can enumerate sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, lithium methoxide, lithium ethoxide, potassium tert.-butoxide etc.These alkoxide can use a kind or use more than 2 kinds.
In the middle of these alkoxide, preferably use sodium methylate or sodium ethylate.The solution (B) that contains alkoxide is to use solvent that dissolves aforementioned alkoxide and the solution that is modulated into normality.
As the dissolving aforementioned alkoxide solvent (below, be called " B1 solvent ".) preferred alcohols.Specifically, can enumerate methyl alcohol, ethanol, Virahol, n-propyl alcohol etc.These alcohol can use a kind or make up more than 2 kinds and to use.In the middle of these, preferably use methyl alcohol or ethanol.
In the solvent (B), with respect to aforementioned alkoxide 100 weight parts, the content of aforementioned B1 solvent is preferably 500～5000 weight parts, 1000～4000 weight parts more preferably.
The solution (C) that contains alcohol
As the solution (C) that contains alcohol, use the independent solvent of alcohol (below, be called " C1 solvent ") or alcohol (C1 solvent) and other solvent (below, be called " C2 solvent ".) mixed solvent.As this alcohol (C1 solvent), can enumerate lower alcohols such as methyl alcohol, ethanol, Virahol, n-propyl alcohol.These alcohol can use a kind or make up more than 2 kinds and to use.In the middle of these alcohol, preferably use methyl alcohol or ethanol.
Alcohol (C1 solvent) dissolving is as the chlorination aza cyclo-butanone derivatives shown in the aforementioned formula (1) of raw material, but do not dissolve the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2) as reaction product.Therefore, as reaction product directly being fit to the reaction solvent that crystal reclaims.
As other solvent (C2 solvent), use solvent as described below, this dissolution with solvents is as the aforementioned chlorination aza cyclo-butanone derivatives of raw material, further is dissolved in impurity such as the chlorination aza cyclo-butanone derivatives of the unreacting material that becomes impurity after reaction finishes or byproduct of reaction.By using such solvent, can from reaction solution, reclaim the 3-chloromethyl-3-Cephem Derivative crystal shown in the aforementioned formula (2) as reaction product with high purity.As the C2 solvent, for example can enumerate ester classes such as methyl-formiate, ethyl formate, ritalin, vinyl acetic monomer, N-BUTYL ACETATE, ethyl propionate; Halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, ethylene dibromide, chlorobenzene; Ethers such as diethyl ether, dibutyl ether, diox, tetrahydrofuran (THF); Nitrile such as acetonitrile, butyronitrile; Hydro carbons such as pentane, hexane, hexanaphthene etc.These solvents can use a kind or make up more than 2 kinds and to use.In the middle of these, preferably use diox.
The blending ratio of alcohol (C1 solvent) and other solvent (C2 solvent) is: with respect to alcohol (C1 solvent) 100 weight parts, other solvent (C2 solvent) is preferably 10～30 weight parts, 10～20 weight parts more preferably.The solution (C) that uses so preferred blending ratio under reaction conditions described later can obtain the crystal of the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2) with high yield and high purity when reacting, so preferred.During other solvent (C2 solvent) less than 10 weight parts, along with reaction is carried out, in the 3-chloromethyl that impurity such as byproduct of reaction are generated by wrapping into-3-Cephem Derivative crystal and become granularly, therefore, be difficult to sometimes obtain 3-chloromethyl-3-Cephem Derivative crystal with high purity and high yield.When surpassing 30 weight parts, the 3-chloromethyl-3-Cephem Derivative dissolution of crystals and the yield that are generated sometimes reduce easily.
With respect to chlorination aza cyclo-butanone derivatives 100 weight parts shown in the aforementioned formula (1), the consumption of solution (C) that contains alcohol is 300～2000 weight parts, is preferably 500～1000 weight parts especially.During less than 300 weight parts, reaction is difficult to carry out and easy sometimes remained unreacted raw material.When surpassing 2000 weight parts, because a large amount of solvent that uses more than the necessary amount, thereby industrial unfavorable sometimes.
Reaction conditions
In the operation 1, the reaction of chlorination aza cyclo-butanone derivatives shown in the aforementioned formula (1) and alkoxide is preferably carried out below pH8, more preferably carries out in pH6～8.The crystal of the 3-chloromethyl-3-Cephem Derivative of reaction product is owing to be extremely unsettled to alkali, thereby pH surpasses at 8 o'clock, decomposes in reaction process, is difficult to obtain with high purity and high yield the 3-chloromethyl-3-Cephem Derivative crystal of target sometimes.
The mensuration of pH in the reaction is preferably: for example take out reaction solution to litmus paper from reaction system, it is dripped water measure; Perhaps, the reaction solution that takes a morsel adds the water of 2 times of amounts to it, then by mensuration such as pH meters.
Be swift in response and carry out.But when having unreacted alkoxide in the reaction system, because alkoxide shows weakly alkaline, thereby the pH of reaction system rises, and tends to alkalescence.Therefore, the aforementioned solution (A) that the reaction in the operation 1 preferably will contain the chlorination aza cyclo-butanone derivatives is added drop-wise in the aforementioned solution (C) that contains alcohol, so that it is in the scope of aforementioned pH with the aforementioned solution (B) that contains alkoxide.
In addition, the dripping quantity of aforementioned solution (A) and aforementioned solution (B) is: make the mol ratio of alkoxide in the solution (B) and the aforementioned chlorination aza cyclo-butanone derivatives in the solution (A) be preferably 0.8～1.5 times of mole, the amount of 1.1～1.2 times of moles more preferably.By being such dripping quantity, in final reaction system, the remaining quantity of the chlorination aza cyclo-butanone derivatives of unreacting material tails off, and obtains 3-chloromethyl-3-Cephem Derivative crystal with high purity and high yield.On the contrary, during 0.8 times of mole of less than, sometimes more than the residual necessary amount of chlorination aza cyclo-butanone derivatives of unreacting material.When surpassing 1.5 times of moles, reaction solution becomes pH and surpasses 8 alkalescence, and the 3-that is generated chloromethyl-3-Cephem Derivative crystal decomposes sometimes easily.
In addition, the dripping quantity of aforementioned solution (A) and aforementioned solution (B) is: the content (A2 solvent+B1 solvent+C1 solvent) of the alcohol of (A1 solvent+A2 solvent+B1 solvent+C1 solvent+C2 solvent) is preferably 30～95 weight %, the amount of 60～90 weight % more preferably in the total reaction solvent of solution (the A)～solution (C) after make to drip finishing.Alcohol in the reaction solvent after drip finishing contain quantity not sufficient 30 weight % the time, the alkoxide of reaction raw materials is difficult to be dissolved in the reaction solution sometimes, in addition, causes 3-chloromethyl-3-Cephem Derivative dissolution of crystals and yield to reduce sometimes.On the other hand, when surpassing 95 weight %, therefore along with reaction is carried out, in the 3-chloromethyl that impurity such as byproduct of reaction are generated by wrapping into-3-Cephem Derivative crystal and become granularly, be difficult to sometimes obtain 3-chloromethyl-3-Cephem Derivative crystal with high purity and high yield.
Use the mixed solvent of diox (A1 solvent) and methyl alcohol and/or ethanol (A2 solvent) as the solvent of the solution that contains aforementioned chlorination aza cyclo-butanone derivatives (A), use methyl alcohol and/or ethanol (B1 solvent) as the solution that contains alkoxide (B), and (C1 solvent) is Yu the mixed solvent of diox (C2 solvent) to use methyl alcohol and/or ethanol as the solvent (C) that comprises alcohol, methyl alcohol and/or alcoholic acid content with (A1 solvent+A2 solvent+B1 solvent+C1 solvent+C2 solvent) in the reaction solvent after the dropping end are 20～60 weight %, especially be that 30～50 weight % are when dripping, can higher yield and high purity obtain the 3-chloromethyl shown in the aforementioned formula (2)-3-Cephem Derivative crystal, therefore preferred especially.
Be added drop-wise to the method that contains in the pure solution (C) as solution that will contain aforementioned chlorination aza cyclo-butanone derivatives (A) and the solution (B) that contains aforementioned alkoxide, can enumerate following 1 and 2 dropping method.
1. this method is: modulate aforementioned solution (A)～(C), in aforementioned solution (C), the mode of going ahead of the rest with respect to aforementioned solution (B) according to aforementioned solution (A), drip continuously or intermittently solution (A) and (B) make in the reaction system pH the method for aforementioned range (below, be called " 1 dropping method ".)。
2. this method is: modulate aforementioned solution (A)～(C), at first, according to normal 5～30 moles of %, the mode of 10～20 moles of % more preferably of being preferably of the reaction of chlorination aza cyclo-butanone derivatives, aforementioned solution (A) is added drop-wise in the solution (C) that contains alcohol, then, surplus solution (A) and solution (B) is added drop-wise to simultaneously the pH that makes in the solution (C) in the reaction system the method for aforementioned range (below, be called " 2 dropping methods ".)。
Aforementioned 1 dropping method is following method: suitably adjust the dropping order that contains the solution (A) of chlorination aza cyclo-butanone derivatives and contain the solution (B) of alkoxide, always in the mode of aforementioned range solution (A) and solution (B) are added drop-wise to the method that contains in the pure solution (C) according to the pH in the reaction system.
Aforementioned 2 dropping method is following method: the solution that contains the chlorination aza cyclo-butanone derivatives (A) of specified amount is added drop-wise in the solution (C) that contains alcohol in advance, make in the reaction system for acid range (for example, pH4), always in the mode of aforementioned range, in system, almost continuously surplus solution (A) and the solution (B) that contains alkoxide are added drop-wise to the method that contains in the pure solution (C) simultaneously according to the pH in the reaction system.
In addition, when modulation contains the solution (C) of alcohol, normal 5～30 moles of %, 10～30 moles of % more preferably of being preferably of the reaction of the aforementioned chlorination aza cyclo-butanone derivatives of adding in the solution (C) that contains alcohol in advance, then, can with the same operation of operation of aforementioned 2 dropping method, the further solution that contains the chlorination azetidinone of dropwise reaction institute necessary amounts and contain the solution of alkoxide simultaneously in the solution (C) that contains alcohol makes the interior pH of reaction system always in aforementioned range.
In the solution (C) that contains alcohol, drip when containing the solution (A) of chlorination aza cyclo-butanone derivatives and containing the solution (B) of alkoxide the possibility of the system that responds alkalitropism side shifting from the beginning simultaneously.Reaction product in the operation 1, to be 3-chloromethyl-3-Cephem Derivative crystal extremely unstable to alkali, and pH 8 decomposes in reaction process when above, therefore, as described above shown in 1 and 2 the dropping method, preferably drip the chlorination aza cyclo-butanone derivatives in advance and react and make reaction system can not move to alkaline side all the time above pH8.In addition, the solution (A) that contains the chlorination aza cyclo-butanone derivatives is for about pH4, contains the solution (B) of alkoxide by interpolation, and the pH of reaction system rises.
In aforementioned 1 and 2 the dropping method, the pH of 2 dropping method control is easy, industrial in this respect particularly advantageous.
In addition, after the solution that will contain raw material chlorination aza cyclo-butanone derivatives (A) all joins in the solution (C) that contains alcohol, dropping contains the solution (B) of alkoxide, below pH8, react, this moment is along with reaction is carried out, in the 3-chloromethyl of the reaction product that impurity is generated by wrapping into-3-Cephem Derivative crystal, the tendency that has quality to reduce.But by this method, existence can obtain the crystalline advantage quickly.Therefore, although the burden of this method in the purification process of back operation becomes many, can carry out with simple operations.
In addition, the reaction in the operation 1 is preferably reacted as the reaction system of reaction solvent by containing diox.The content of diox along with reaction is carried out, in the reaction product 3-chloromethyl that impurity such as byproduct of reaction are generated by wrapping into-3-Cephem Derivative crystal, becomes granular after a little while easily.Therefore, with respect to chlorination aza cyclo-butanone derivatives 100 weight parts, the content of De diox preferably maintains the scope of 10～30 weight parts in the reaction system.
In temperature of reaction is when carrying out previous reaction below 5 ℃, can suppress the generation of by product and obtain the 3-chloromethyl-3-Cephem Derivative crystal shown in the aforementioned formula (2) of target with high yield, so preferred.On the other hand, in the time of not enough-20 ℃, raw material, impurity are separated out easily, therefore preferably-20～5 ℃, particularly under-10～5 ℃, react.
By such operation, along with the carrying out of reaction, the reaction soln gonorrhoea can see at any time that thus the 3-chloromethyl-3-Cephem Derivative crystalline shown in the aforementioned formula (2) of target separates out.After reaction finished, neutralization, filtration, drying obtained crystal.Also can purify by washing, recrystallization as required.In addition, the R in the aforementioned formula (2)
1, R
2Identical with in the aforementioned formula (1).
As the solvent that can in washing and recrystallization, use, for example can enumerate alcohol such as methyl alcohol, ethanol, Virahol, n-propyl alcohol, nitriles such as acetonitrile, butyronitrile, ketones such as acetone, methylethylketone, amidess such as dimethyl formamide, diethylformamide etc.These solvents can suitably select to use a kind or use more than 2 kinds.
Then, operation 2 is described.In the operation 2, make crystal and the triphenylphosphine and the sodium iodide reaction of the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2) that obtains in the operation 1, obtain the 3-triphenyl phosphonium iodide methyl-3-cephem compounds shown in the following general formula (3).In addition, the R in the aforementioned formula (3)
1, R
2Identical with in the aforementioned formula (2).
(in the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl.)
By aforementioned formula (2) and (3) as can be known, the reaction in the operation 2 is that the chlorine atom that will replace on 3 methyl of the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2) is transformed into the triphenyl phosphonium iodide.Below the example of this reaction conditions is set forth.
Reaction can be under normal pressure, 25～40 ℃, carried out 1～4 hour.Reactive ratio is: with respect to 1 mole of the 3-chloromethyl shown in the aforementioned formula (2)-3-Cephem Derivative, 1～1.5 mole of triphenylphosphine, 1～1.5 mole of sodium iodide.
Reaction can be carried out in chloroform, methylene dichloride equal solvent.Can contain water in the solvent.Therefore, to can be used as concentration be that the aqueous solution about 10～100g/L uses to aforementioned sodium iodide.In addition, with respect to crystal 100 weight parts of the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2), the consumption of solvent is preferably 500～1000 weight parts.
Then, operation 3 is described.In the operation 3, make 3-triphenyl phosphonium iodide methyl-3-cephem compounds and sodium hydroxide or the reaction of sodium bicarbonate shown in the aforementioned formula (3) that obtains in the operation 2, obtain the 3-[(triphenylphosphine shown in the aforementioned formula (I)) methyl]-the 3-cephem compounds.Below the example of the condition of this reaction is set forth.
Reaction is for example under normal pressure, carried out 0.1～3 hour at-5～20 ℃.In addition, reactive ratio is: with respect to 1 mole of the 3-triphenyl phosphonium iodide methyl shown in the aforementioned formula (3)-3-cephem compounds, and 1～3 mole of preferred sodium hydroxide or sodium bicarbonate.
Reaction can be carried out in chloroform, methylene dichloride equal solvent.Can contain water in the solvent.Therefore, to can be used as concentration be that the aqueous solution about 10～30g/L uses for aforementioned sodium hydroxide or sodium bicarbonate.In addition, with respect to 3-triphenyl phosphonium iodide methyl-3-cephem compounds 100 weight parts shown in the aforementioned formula (3), the consumption of solvent is preferably 500～1000 weight parts.When in two phase systems that comprise hydrophobic organic solvents such as chloroform, methylene dichloride and water, reacting, reaction separates organic layer after finishing with water layer, this organic layer that only will contain the positive phosphine compound shown in the aforementioned formula (I) is used for the manufacture method of cephem compounds of the present invention.
Be used as the positive phosphine compound shown in the aforementioned formula (I) of initial substance in the manufacture method of cephem compounds of the present invention, the preferred use carried out the material that above operation 1～3 obtains.But, in addition, also can use the following material that obtains: use the chlorination aza cyclo-butanone derivatives shown in the aforementioned formula of using in the aforementioned operation 1 (1), the operation that replaces aforementioned operation 1 and carry out the record of Japanese kokai publication sho 58-74689 communique, after obtaining the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2), carry out the material that aforementioned operation 2,3 obtains.
Embodiment
Below, the present invention will be described in more detail by embodiment.But scope of the present invention is not limited to this embodiment.
Embodiment 1
Operation 1
According to following reaction formula,, carry out the reaction of operation 1 according to following order.In addition, in reaction formula shown below, Bn represents that benzyl, PMB represent methoxy-benzyl, Ph are represented phenyl.
Operation 1
Compound (1) compound (2)
With 68.6g (0.052 mole) contain 47.7 weight % compounds (1) De dioxane solution join nitrogen replacement dropping funnel in, add 50g dehydration methyl alcohol (Northeast chemistry reagent) dilution and make A liquid.
4.46g (0.063 mole) sodium ethylate is dissolved in the 103g methyl alcohol, and modulation contains the methanol solution of 4 weight % sodium ethylates, makes B liquid.
Use in the flask in the reaction of four-hole, add the 13g diox with solvent, further add the 160mL dewatered ethanol, be cooled to-2～2 ℃ as reaction.To 1/8 amount (pH4) of wherein adding above-mentioned A liquid total amount.
Then, the limit drips remaining above-mentioned A liquid and above-mentioned B liquid simultaneously with the temperature maintenance of reaction system on-2～2 ℃ of limits.When dripping about about 1/5 B liquid, reaction solution begins gonorrhoea, becomes the slurry that comprises white crystal.Further, the limit continues to drip simultaneously A liquid and B liquid with the temperature maintenance of reaction system on-2～2 ℃ of limits, drips through about 4 hours and finishes (pH7～8).After drip finishing, further under agitation, carry out reaction in 0.25 hour at 0 ℃.
After reaction finishes, in reaction solution, add 0.44g acetic acid and neutralize.In addition, the pH of the reaction system after the neutralization is 4～5.After the neutralizing treatment, further, former state stirs under 0.5 hour at-2～2 ℃ carries out slaking.
After slaking finishes, filter, with ice-cooled 18g washed with methanol, further, use the methanol solution 36g of the water that comprises 30 weight % to carry out the 2nd flushing, the 3rd the ice-cooled 18g washed with methanol of usefulness the gained filter cake with the 3G glass filter.
The cake that carrying out washing treatment is crossed is put in the moisture eliminator, at room temperature used vacuum pump dry evening, obtain the compound (2) of 21.8g (purity 94.3%, yield 81.2%) as target compound.Gained compound (2) is identified by various analyses.Appraising datum below is shown.
Appraising datum
·
1H-NMR(δ，CDCl
3)3.41(1H，d，j＝18.5)、3.59(1H，d，j＝18.5)、4.92(1H，d，j＝4.9)、5.82(1H，d，d，j＝4.9，9.3)、6.12(1H，d，j＝9.3)、3.58(1H，d，j＝16.1)、3.67(1H，d，j＝16.1)、7.40-7.28(5H，m)、4.39(1H，d，j＝11.9)、4.50(1H，d，j＝11.9)、5.20(2H，s)、7.32(2H，d，j＝8.6)、6.88(2H，d，j＝8.6)、3.80(3H，s)
·FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
·FAB-MS
M+1：487m/z
Operation 2
According to following reaction formula,, carry out the reaction of operation 2 according to following order.
Operation 2
Compound (2) compound (3)
Dissolving triphenylphosphine in chloroform (pure reagent superfine, 200mL) (Northeast chemistry reagent superfine, 18.7g) adds the compound (2) that obtains in the aforementioned operation 1 of 33.3g in this solution.To wherein adding the aqueous solution (ion exchanged water, 200mL) that contains sodium iodide (Northeast chemistry reagent superfine, 10.7g), obtain 2 layers of solution.The limit is stirred this solution limit reaction solution is heated to 32 ± 1 ℃ and react, and obtains the compound (3) as target compound.In addition, reaction is carried out until confirming that with HPLC raw material disappears.
Operation 3
According to following reaction formula,, carry out the reaction of operation 3 according to following order.
Operation 3
Compound (3) compound (4)
The reaction solution of the compound that obtains from comprise operation 2 (3) is discarded water layer, and the gained organic layer is cooled to 3 ± 1 ℃.The aqueous solution (ion exchanged water, 200mL) that then will comprise sodium hydroxide (Northeast chemistry reagent superfine, 3.15g) joins above-mentioned organic layer, makes its reaction 30 minutes under 3 ± 1 ℃ temperature, obtains the compound (4) as target compound.
Operation 4
According to following reaction formula,, carry out the reaction of operation 4 according to following order.
Operation 4
The reaction solution of the compound that obtains from comprise operation 3 (4) is discarded water layer, appends ethylene glycol and make that the volume ratio of chloroform and ethylene glycol is 10: 0.5 in the bolarious chloroformic solution of gained.Then, this reaction solution is cooled to-15 ± 1 ℃.React to wherein adding 65.8g 4-methylthiazol-5-formaldehyde, obtain compound (A).
In the reaction, the temperature of reaction solution is controlled at-15 ± 1 ℃, suitably the carrying out by the reaction of HPLC analysis confirmation.Its result, from reaction begin with 18 hours compound (4) by completely consumed, therefore with this as reaction end.
In addition, above-mentioned 4-methylthiazol-5-formaldehyde be with after 2-(4-methyl-5-thiazole) ethylhexoate (Tokyo the changes into reagent) hydrolysis, oxidation and synthetic.
By target HPLC quantitative analysis in using, the reaction yield of the target compound Z body of obtaining at reaction end (compound (A)) is 87.4%.
In addition, the isomer E body burden of this moment being used ratio E/Z (=(the HPLC area of the HPLC area/Z body of E body) * 100) when expression with respect to the E body burden of Z body burden, is 3.13%.
HPLC analyzes by following condition and implements.
Post: YMC-Pack ODS-A AA12S05-1506WT
Moving phase: 50mM phosphoric acid buffer: acetonitrile=1: 1
Detect wavelength: 274nm
Reaction solution after the reaction end is washed with saturated metabisulfite solution, then, reclaim chloroform and also add methyl alcohol, carry out crystallization.Filter by glass filter and to reclaim the crystal that is produced, use vaporizer to implement dry and separating compound (A).
Embodiment 2～5
As shown in table 1, the condition (volume ratio of the kind of employed lower alcohol, chloroform and lower alcohol, temperature of reaction, reaction concluding time) of change operation 4, in addition, operation 1～4 is carried out in operation similarly to Example 1, obtains the compound (A) as the Z body.The reaction yield of the Z body of the HPLC quantitative analysis carried out of operation and E body burden the results are shown in table 1 similarly to Example 1.The condition and the result of the operation 4 among the embodiment 1 also are shown in the table 1 in addition, in the lump.
Table 1
| Lower alcohol | Chloroform: lower alcohol | Temperature of reaction (℃) | The reaction concluding time (h) | Z body yield (%) | E body burden (%) | |
| Embodiment 1 | Ethylene glycol | ??10∶0.5 | ??-15±1 | ??18 | ??87.4 | ??3.13 |
| Embodiment 2 | Ethylene glycol | ??10∶0.2 | ??-20±1 | ??22 | ??88.1 | ??2.93 |
| Embodiment 3 | 1, the 2-propylene glycol | ??10∶1 | ??-15±1 | ??19 | ??86.0 | ??3.62 |
| Embodiment 4 | 1, ammediol | ??10∶1 | ??-10±1 | ??12 | ??87.1 | ??3.51 |
| Embodiment 5 | Ethylene glycol monomethyl ether | ??10∶1 | ??-20±1 | ??18 | ??90.3 | ??2.76 |
Embodiment 6
In the operation 4, replacement ethylene glycol as shown in table 2 and use n-propyl alcohol changes volume ratio, temperature of reaction and the reaction concluding time of chloroform and n-propyl alcohol, in addition, operates similarly to Example 1 and carries out operation 1～4, obtains the compound (A) as the Z body.
The output of the target compound Z body of obtaining at reaction end by HPLC quantitative analysis similarly to Example 1 (compound (A)) is 34.04g.This is equivalent to reaction yield is 88.6%.The isomer E body burden of this moment is 3.76% when representing with E/Z.
Reaction solution after the reaction end is washed with saturated metabisulfite solution, then, reclaim chloroform and also add methyl alcohol, carry out crystallization.Filter by glass filter and to reclaim the crystal that is produced, use vaporizer to carry out drying, isolate the compound (A) of 34.52g, this is equivalent to yield is 89.8%.By the quality of the HPLC analysis confirmation isolated compound (A) of condition similarly to Example 1, isomer E body burden is 1.86% when representing with E/Z, does not detect the impurity of E body class, can be confirmed to be few high-quality of foreign matter content.
Embodiment 7
Use aforesaid compound (1) as initial substance, make aforesaid compound (2) according to following order (below, be also referred to as operation 1 ').
With 71.48g (0.104 mole) compound (1) under nitrogen atmosphere, be dissolved among the dry DMF of 640mL, be cooled to-30 ℃.Then, under-30～-20 ℃, drip 28% ammoniacal liquor 17.76g (0.292 mole is equivalent to 2.8 times of moles) bit by bit.Drip the back-30～-20 ℃ of slakings 1 hour.
After reaction finishes, after adding 5 weight % hydrochloric acid are adjusted to 4～5 with pH in reaction solution, add the 1.92L vinyl acetic monomer, separate organic layer at 0 ℃.Then, isolating organic layer with saturated common salt water washing 2 times, is further added anhydrous sodium sulphate and dewaters in this organic layer.
Then, the organic layer after under reduced pressure concentrated this dehydration obtains 38.0g (purity 93.3%, yield 70.0%) buttery compound (2).Gained compound (2) is identified by various analyses.Appraising datum below is shown.
Appraising datum
·
1H-NMR(δ，CDCl
3)3.41(1H，d，j＝18.5)、3.59(1H，d，j＝18.5)、4.92(1H，d，j＝4.9)、5.82(1H，d，d，j＝4.9，9.3)、6.12(1H，d，j＝9.3)、3.58(1H，d，j＝16.1)、3.67(1H，d，j＝16.1)、7.40-7.28(5H，m)、4.39(1H，d，j＝11.9)、4.50(1H，d，j＝11.9)、5.20(2H，s)、7.32(2H，d，j＝8.6)、6.88(2H，d，j＝8.6)、3.80(3H，s)
·FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
·FAB-MS
M+1：487m/z
Use gained compound (2), under the condition identical, implement the reaction of (operation 2)～(operation 4), obtain target compound Z body (compound (A)) with embodiment 6.
Be implemented in the HPLC quantitative analysis of the target compound Z body (compound (A)) of reaction end, the Z body is 33.58g (reaction yield 87.4%), is 5.67% when the E body burden is represented with E/Z.This moment is with embodiment 6 relatively the time, and the reaction yield of embodiment 7 is low to moderate approximately 1.4% as can be known, has generated more impurity E body, about 1.9%.
Embodiment 8～13
As shown in table 2, the condition (volume ratio of chloroform and n-propyl alcohol, temperature of reaction, reaction concluding time) of change operation 4, in addition, operation 1～4 is carried out in operation similarly to Example 6, obtains the compound (A) as the Z body.The reaction yield of the Z body of the HPLC quantitative analysis of carrying out similarly to Example 1 and E body burden the results are shown in table 2.The condition and the result of embodiment 6 and 7 also are shown in the table 2 in addition, in the lump.
Table 2
| Compound (2) | Chloroform: n-propyl alcohol | Temperature of reaction (℃) | The reaction concluding time (h) | Z body yield (%) | E body burden (%) | |
| Embodiment 6 | Operation is made by operation 1 similarly to Example 1 | ??10∶1 | ??-15±1 | ??18 | ??88.6 | ??3.76 |
| Embodiment 7 | Make by operation 1 ' | ??10∶1 | ??-15±1 | ??18 | ??87.4 | ??5.67 |
| Embodiment 8 | Operation is made by operation 1 similarly to Example 1 | ??10∶1 | ??-10±1 | ??14 | ??83.7 | ??4.45 |
| Embodiment 9 | ??″ | ??10∶1 | ??-20±1 | ??26 | ??86.2 | ??3.50 |
| Embodiment 10 | ??″ | ??10∶0.5 | ??-5±1 | ??18 | ??83.8 | ??4.57 |
| Embodiment 11 | ??″ | ??10∶0.5 | ??0±1 | ??12 | ??81.2 | ??4.93 |
| Embodiment 12 | ??″ | ??10∶0.2 | ??-5±1 | ??22 | ??82.2 | ??4.56 |
| Embodiment 13 | ??″ | ??10∶0.2 | ??0±1 | ??18 | ??80.8 | ??5.25 |
Comparative example 1～4
In the comparative example 1～3, the condition of change operation 4 as shown in table 3 (volume ratio of the kind of lower alcohol, chloroform and lower alcohol, temperature of reaction, reaction concluding time), in addition, operation 1～4 is carried out in operation similarly to Example 6, obtains the compound (A) as the Z body.In the comparative example 4, the condition of change operation 4 as shown in table 3, in addition, operation 1 ' and operation 2～4 are carried out in operation similarly to Example 7, obtain the compound (A) as the Z body.The reaction yield of the Z body of the HPLC quantitative analysis carried out of operation and E body burden the results are shown in table 3 similarly to Example 1.
Table 3
| Lower alcohol | Chloroform: lower alcohol | Temperature of reaction (℃) | The reaction concluding time (h) | Z body yield (%) | E body burden (%) | |
| Comparative example 1 | Ethylene glycol | ??10∶0 | ??-15±1 | ??48 *1 | ??76.3 | ??2.86 |
| Comparative example 2 | Ethylene glycol | ??10∶2 | ??-15±1 | ??10 | ??79.6 | ??5.91 |
| Comparative example 3 | Ethylene glycol | ??10∶1 | ??10±1 | ??4 | ??72.8 | ??8.33 |
| Comparative example 4 | N-propyl alcohol | ??10∶2 | ??-15±1 | ??14 | ??82.1 | ??6.02 |
* 1: 48 little fashion are not finished reaction, industrial unfavorable.
Industrial utilizability
Such as described in detail above, according to the present invention, can provide selectively and make with high yield method as the Z body of the useful cephem compounds of the synthetic intermediate of cephalosporins.
Claims (3)
1. the manufacture method of a cephem compounds, it is characterized in that, hydrochloric ether and lower alcohol with the volume ratio below 10: 1 (the former: in the mixed solvent that the latter) mixes, make the 3-[(triphenylphosphine shown in the following general formula (I)) methyl]-the 4-methylthiazol-5-formaldehyde shown in 3-cephem compounds and the following formula (II) is+5 ℃～-50 ℃ reactions, obtain the 3-[2-shown in the following general formula (A) (4-methylthiazol-5-yl) vinyl]-the 3-cephem compounds
In the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl,
In the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl.
2. the manufacture method of cephem compounds according to claim 1, aforementioned lower alcohol is a glycols.
3. the manufacture method of cephem compounds according to claim 1, it is by carrying out following operation 1～3 successively, obtain the 3-[(triphenylphosphine shown in the aforementioned formula (I)) methyl]-the 3-cephem compounds after, make the 3-[(triphenylphosphine of gained) methyl]-the 4-methylthiazol-5-formaldehyde reaction shown in 3-cephem compounds and the aforementioned formula (II)
Operation 1: chlorination aza cyclo-butanone derivatives shown in the following general formula (1) and alkoxide are reacted below pH8 in the solvent that comprises alcohol, obtain the crystal of the 3-chloromethyl-3-Cephem Derivative shown in the following general formula (2),
In the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl, R
3Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue,
In the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl,
Operation 2: make crystal and the triphenylphosphine and the sodium iodide reaction of the 3-chloromethyl-3-Cephem Derivative shown in the aforementioned formula (2) that obtains in the operation 1, obtain the 3-triphenyl phosphonium iodide methyl-3-cephem compounds shown in the following general formula (3),
In the formula, R
1, R
2Expression replaces or unsubstituted aromatic hydrocarbyl,
Operation 3: make 3-triphenyl phosphonium iodide methyl-3-cephem compounds and sodium hydroxide or the reaction of sodium bicarbonate shown in the aforementioned formula (3) that obtains in the operation 2, obtain the 3-[(triphenylphosphine shown in the aforementioned formula (I)) methyl]-the 3-cephem compounds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008223035 | 2008-09-01 | ||
| JP2008223035 | 2008-09-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101665499A true CN101665499A (en) | 2010-03-10 |
Family
ID=41802302
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910118653A Pending CN101665499A (en) | 2008-09-01 | 2009-02-27 | Manufacturing process for cephem compounds |
| CN 200910171281 Expired - Fee Related CN101665500B (en) | 2008-09-01 | 2009-09-01 | Manufacturing process for cephem compounds |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910171281 Expired - Fee Related CN101665500B (en) | 2008-09-01 | 2009-09-01 | Manufacturing process for cephem compounds |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP4659110B2 (en) |
| CN (2) | CN101665499A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107033162B (en) * | 2016-02-03 | 2020-05-01 | 湖北凌晟药业有限公司 | Preparation of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester |
| CN105622636B (en) * | 2016-02-05 | 2017-08-25 | 河南理工大学 | A kind of preparation method of Cefditoren pivoxil Cephalosporins intermediate |
| CN106083893B (en) * | 2016-07-04 | 2018-06-29 | 湖北凌晟药业有限公司 | 7- phenylacetylamino -3- acrylic -4- cephemcarboxylic acids are to the preparation method of methoxy benzyl ester |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO120261B1 (en) * | 1997-06-24 | 2005-11-30 | Meiji Seika Kaisha Ltd. | Process for the selective preparation of z-isomer of 3-(2-substituted vinyl)cephalosporin |
| CN1282652C (en) * | 2002-04-22 | 2006-11-01 | 日本化学工业株式会社 | Method for producing crystal of 3-chloromethyl-3-cephem derivative |
| US7459550B2 (en) * | 2003-07-04 | 2008-12-02 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of Cefditoren |
-
2009
- 2009-02-27 CN CN200910118653A patent/CN101665499A/en active Pending
- 2009-08-19 JP JP2009189664A patent/JP4659110B2/en not_active Expired - Fee Related
- 2009-09-01 CN CN 200910171281 patent/CN101665500B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101665500A (en) | 2010-03-10 |
| JP2010077115A (en) | 2010-04-08 |
| CN101665500B (en) | 2013-06-26 |
| JP4659110B2 (en) | 2011-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102372728B (en) | Synthesizing method for cephalosporin compound | |
| CN106866668B (en) | The method of one kettle way preparation AVM hereinafter Batan sodium | |
| CN102753531A (en) | Method for producing 1-alkyl-/1-aryl-5-pyrazole-carboxylic acid derivatives | |
| CN101665500B (en) | Manufacturing process for cephem compounds | |
| CN109180704A (en) | A kind of synthetic method of Cefditoren pivoxil Cephalosporins | |
| CN103282355A (en) | Method for producing alpha -mino-gamma-butyrolactone | |
| CN107880042A (en) | The preparation method of AVM hereinafter Batan sodium and its midbody compound | |
| CN109485659A (en) | The preparation method of 7 alpha-alkoxy base oxacephem intermediates | |
| CN101993450B (en) | Preparation method of cefoselis sulfate | |
| CN103804414B (en) | For the preparation of rosuvastain calcium midbody compound and prepared the method for rosuvastain calcium by it | |
| JP4481829B2 (en) | Novel synthetic intermediate of carbapenem compound for oral administration and process for producing the same | |
| CN102174047A (en) | Novel process for preparing doripenem | |
| CN105593200B (en) | The manufacture method and α bromoacetophenone compounds of α halo acetophenone compounds | |
| CN104098604B (en) | A kind of method preparing fosaprepitant dimeglumine | |
| KR101608539B1 (en) | Process for the preparation of cephem compounds | |
| CN100398547C (en) | Process for producing 3-chloromethyl-3-cephem derivative | |
| WO2008127070A1 (en) | Process for stereoselective preparation of 4-bma using a chiral auxiliary | |
| CN101754971A (en) | Process for producing phosphine oxide vitamin D precursors | |
| CN1315841C (en) | An improved process for the preparation of chloro methyl cephem derivatives | |
| CN102659713A (en) | Preparation method for cefdinir side-chain acid active ester | |
| CN109206426A (en) | The preparation method of Pyrazolopyrimidines | |
| KR100650207B1 (en) | Glutaryl 7-amino-3-vinyl-cephalosporanic acid derivatives and process for preparing it | |
| FI71562B (en) | FOERFARANDE FOER FRAMSTAELLNING AV 6-BETA-SUBSTITUERADE PENICILLANSYRA DERIVAT OCH SAOSOM MELLANPRODUKTER ANVAENDBARA 6-PERFLUORALKYLSULFONYLOXIPENICILLANSYRADERIVAT | |
| WO2022153626A1 (en) | Method for manufacturing heterocycle-containing amino acid compound | |
| CN1187322C (en) | Method for producing aryl-iminomethyl-carbamic acid esters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20100310 |