CN108047251B - The recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution - Google Patents
The recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution Download PDFInfo
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- CN108047251B CN108047251B CN201711408097.XA CN201711408097A CN108047251B CN 108047251 B CN108047251 B CN 108047251B CN 201711408097 A CN201711408097 A CN 201711408097A CN 108047251 B CN108047251 B CN 108047251B
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- phenylacetamide
- distillate
- methoxybenzyl ester
- crystalline mother
- acid
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- 150000002148 esters Chemical class 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 26
- 239000010413 mother solution Substances 0.000 title claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 108
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 91
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 46
- 235000019441 ethanol Nutrition 0.000 claims abstract description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000243 solution Substances 0.000 claims abstract description 26
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 238000004821 distillation Methods 0.000 claims abstract description 13
- 239000012452 mother liquor Substances 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000010792 warming Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 25
- -1 sodium alkoxide Chemical class 0.000 claims description 9
- LSBDFXRDZJMBSC-UHFFFAOYSA-N Amide-Phenylacetic acid Natural products NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims description 6
- 238000010025 steaming Methods 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 claims description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 11
- 230000008025 crystallization Effects 0.000 abstract description 11
- 238000011084 recovery Methods 0.000 abstract description 5
- 230000036632 reaction speed Effects 0.000 abstract description 3
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 abstract description 2
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 abstract description 2
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 abstract description 2
- KFCMZNUGNLCSJQ-NFBKMPQASA-N (4-methoxyphenyl)methyl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-NFBKMPQASA-N 0.000 description 8
- 230000018044 dehydration Effects 0.000 description 7
- 238000006297 dehydration reaction Methods 0.000 description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000001577 simple distillation Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- NVIAYEIXYQCDAN-MHTLYPKNSA-N (6r,7s)-7-azaniumyl-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(C)=C(C([O-])=O)N2C(=O)[C@H]([NH3+])[C@@H]12 NVIAYEIXYQCDAN-MHTLYPKNSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
A kind of recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution, is related to staurosporine medical intermediate technical field.The following steps are included: (1), by the mixed alcohol crystalline mother solution of the methanol of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester and ethyl alcohol, distillation, the distillate volume steamed is the 90 ± 2% of total mother liquor volume；(2) distillate of step (1) is transferred to dehydrating kettle, detects distillate moisture, the methanol solution of sodium methoxide and/or the ethanol solution of sodium ethoxide is added, reacted 10-15 minutes；(3) ethyl acetate is added into dehydrating kettle, is warming up to 50 ± 2 DEG C, reacts 2 ± 1 hours；(4) after reaction, air-distillation；(5) distillate is received, moisture and content are detected, moisture control is 0.05vt% hereinafter, using for 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystallization preparation.The advantages that the method has easy to operate, and reaction speed is fast, at low cost, and the rate of recovery is high, and equipment investment is small, safe.
Description
Technical field
The present invention relates to staurosporine medical intermediate technical field, especially a kind of 7- phenyl acetamide -3- chloromethyl
Recoverying and utilizing method of the cephalosporanic acid to methoxy benzyl ester crystalline mother solution.
Background technique
7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester, abbreviation GCLE are among the important cephalo of one kind
Body, with the big cephalosporin nucleus of 7-ACA, 7-ADCA and referred to as three.
The recrystallisation solvent recycling of GCLE is to influence the key factor of product cost, DMF and ethyl acetate aqueous systems, DMF and
Methanol aqueous systems, methanol system and methanol and alcohol mixed solvent crystallizing system, are the industrial common knots of current GCLE
Crystal system.Wherein DMF system dicyandiamide solution is complicated, and cost recovery is high, influences the manufacturing cost of GCLE, methanol system production
The related substance of GCLE product is exceeded.Methanol and alcohol mixed solvent system are to produce common recrystallisation solvent system at present, still
Due to also containing dioxane in methanol and ethyl alcohol mixed crystallization system, relatively difficult, the separation needs of methanol and ethyl alcohol are recycled
Rectifying column and extraction azeotropic distillation, rectifying device investment is larger, and complicated for operation, energy consumption is high, at high cost, and methanol and ethyl alcohol are still not
It can be kept completely separate.
Chinese patent CN200810100620, it was recently reported that recrystallisation solvent can be used methanol, ethyl alcohol, toluene, methylene chloride or
The mixing of two kinds of solvents of any of them, but there is no the recycling application methods for proposing solvent.
Chinese patent CN201110210754, it was recently reported that chlorination closed loop crystallizes the process route of one-step method, recrystallisation solvent list
Methanol or ethyl alcohol are solely used, using a kind of solvent crystallization, solvent recovery is simple, and convenient for operation, but product quality is affected,
Overall cost qualitative factor is crystallized using methanol and alcohol mixed solvent, and a kind of suitable recovery method of reselection is to solve
The key of GCLE production cost and quality.
Chinese patent CN201510982756, it was recently reported that use metallic sodium and magnesium metal, remove GCLE mixed alcohol crystalline mother solution
The minimizing technology of moisture, the mixed alcohol steamed after dehydration are directly used in the use of GCLE crystallization process, which uses
Metallic sodium, not easy to store, inflammable, dehydration is violent, and there are security risks；Magnesium metal reaction speed is slow, and energy consumption is high, dehydration effect
Fruit is poor, it is difficult to take off the moisture of mixed alcohol to 0.05vt%.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of 7- phenyl acetamide -3- chloromethyl cephalosporanics to methoxybenzyl
The recoverying and utilizing method of ester crystalline mother solution, the method have easy to operate, and reaction speed is fast, at low cost, and the rate of recovery is high, and equipment is thrown
Provide it is small, it is safe the advantages that.
In order to solve the above technical problems, the technical solution used in the present invention is: a kind of 7- phenyl acetamide -3- chloromethyl head
Recoverying and utilizing method of the spore alkanoic acid to methoxy benzyl ester crystalline mother solution, comprising the following steps:
(1) mixed alcohol of the methanol of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester and ethyl alcohol is crystallized
Mother liquor, distillation, the distillate volume steamed are the 90 ± 2% of total mother liquor volume；
(2) distillate of step (1) is transferred to dehydrating kettle, detects distillate moisture, be added sodium methoxide methanol solution and/
Or the ethanol solution of sodium ethoxide, it reacts 10-15 minutes；
(3) ethyl acetate is added into dehydrating kettle, is warming up to 50 ± 2 DEG C, reacts 2 ± 1 hours；
(4) after reaction, air-distillation；
(5) distillate is received, moisture and content are detected, moisture control is 0.05vt% hereinafter, being used for 7- phenyl acetamide -3-
Chloromethyl cephalosporanic crystallizes preparation to methoxy benzyl ester and uses.
Preferably, in (2) step, sodium methoxide mass percentage content is 5%-50% in the methanol solution of sodium methoxide；Second
Sodium ethoxide mass percentage content is 5%-50% in the ethanol solution of sodium alkoxide.
It is further preferred that sodium methoxide mass percentage content is 30% in the methanol solution of sodium methoxide in (2) step；
Sodium ethoxide mass percentage content is 20% in the ethanol solution of sodium ethoxide.
Preferably, in (2) step, total Water molar ratio is 1:1, room in the amount and distillate of sodium methoxide and/or sodium ethoxide
Temperature is stirred to react 10-15 minutes.
Preferably, in (3) step, ethyl acetate additional amount and sodium methoxide and/or sodium ethoxide molar ratio are 1:1.
Preferably, in (4) step, the amount of steaming is the 95 ± 2% of kettle internal solvent volume total amount, and vapo(u)rizing temperature controls in kettle
90 ± 2 DEG C of temperature.
When mother liquor amount of the present invention reaches 9000L, processing is primary；
(2) in step, distillate moisture is suitble to the invention patent in 0.5vt% to 10vt%；
(4) in step, in the raffinate after dehydration distillation, contain sodium acetate, can be recycled.
Design philosophy of the invention is: with the methanol of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester and
The mixed alcohol crystalline mother solution of ethyl alcohol is raw material, and pretreatment desalination and residue are slightly steamed by mother liquor, molten using the methanol of sodium methoxide
The ethanol solution dehydration of liquid and/or sodium ethoxide distills solvent after ethyl acetate removes free alkali, detects moisture and contains
After amount, the crystallization that can be used to 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester prepares solvent.
The beneficial effects of adopting the technical scheme are that
(1) recovered solvent moisture of the present invention is can be controlled under 0.05vt%, can be used for 7- phenyl acetamide -3- chloromethyl
Cephalosporanic acid prepares solvent to methoxy benzyl ester crystallization.
(2) solvent process flow of the present invention is simple, easy to operate, safety, and equipment investment is small.
(3) it after using the dehydration recycling of the ethanol solution of the methanol solution of sodium methoxide or sodium ethoxide, is adjusted with methanol and ethyl alcohol
After bulk solvent ratio, it can be directly used for 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystallization preparation and use,
Substantially reduce the manufacturing cost of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester.
(4) using the ethanol solution mixed dehydration of the methanol solution of sodium methoxide and sodium ethoxide, it ensure that the ratio of methanol and ethanol
It is consistent with thick steaming liquid, bulk solvent proportion is not influenced.Due to the introducing of ethyl alcohol and methanol, parent solution solvents centrifugation is compensated for, it is thick to steam,
The loss of process, without being supplemented novel solvent.
(5) the method for the present invention has good application prospect.
Specific embodiment
The present invention will be further described in detail with reference to the specific embodiments.
Embodiment 1
A kind of recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution, packet
Include following steps:
(1) mixing of the methanol and ethyl alcohol of about 9000L 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester
Alcohol crystalline mother solution is pumped into 10000L reaction kettle, slowly opens collet steam valve, by mother liquor simple distillation, removes residue and salt；
Steam temperature in the kettle be 90 DEG C when, stop distillation, the distillate volume about 8280L steamed (for the 92% of total mother liquor volume)；
(2) distillate of step (1) is transferred in 10000L dehydrating kettle, detects distillate moisture, moisture 0.5vt% is left
Methanol solution 414.2kg (wherein, the amount and distillate of sodium methoxide for the sodium methoxide that mass percentage content is 30% is added in the right side
Middle total Water molar ratio is 1:1), reaction 10 minutes is stirred at room temperature；
(3) ethyl acetate 202.7kg (ethyl acetate additional amount is 1:1 with sodium methoxide molar ratio) is added into dehydrating kettle,
50 ± 2 DEG C are warming up to, is reacted 2 hours；
(4) after reaction, quickly by the solvent air-distillation in dehydrating kettle, the amount of steaming is kettle internal solvent volume total amount
95%, vapo(u)rizing temperature is controlled at 90 ± 2 DEG C of temperature in the kettle, and White residule puts bucket in kettle, is sodium acetate；
(5) distillate is received, detection moisture is 0.03vt%, and supplementing new ethyl alcohol adjustment methanol/ethanol ratio is primary crystallization
Ratio is used for 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystallization preparation.
Embodiment 2
A kind of recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution, packet
Include following steps:
(1) mixing of the methanol and ethyl alcohol of about 9000L 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester
Alcohol crystalline mother solution is pumped into 10000L reaction kettle, slowly opens collet steam valve, by mother liquor simple distillation, removes residue and salt；
Steam temperature in the kettle be 90 DEG C when, stop distillation, the distillate volume about 8100L steamed (for the 90% of total mother liquor volume)；
(2) distillate of step (1) is transferred in 10000L dehydrating kettle, detects distillate moisture, moisture 0.5vt% is left
Ethanol solution 765.6kg (wherein, the amount and distillate of sodium ethoxide for the sodium ethoxide that mass percentage content is 20% is added in the right side
Middle total Water molar ratio is 1:1), reaction 15 minutes is stirred at room temperature；
(3) ethyl acetate 198.2kg (ethyl acetate additional amount is 1:1 with sodium ethoxide molar ratio) is added into dehydrating kettle,
50 ± 2 DEG C are warming up to, is reacted 2 hours；
(4) after reaction, quickly by the solvent air-distillation in dehydrating kettle, the amount of steaming is kettle internal solvent volume total amount
93%, vapo(u)rizing temperature is controlled at 90 ± 2 DEG C of temperature in the kettle, and White residule puts bucket in kettle, is sodium acetate；
(5) distillate is received, detection moisture is 0.04vt%, and supplementing new methanol adjustment methanol/ethanol ratio is primary crystallization
Ratio is used for 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystallization preparation.
Embodiment 3
A kind of recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution, packet
Include following steps:
(1) mixing of the methanol and ethyl alcohol of about 9000L 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester
Alcohol crystalline mother solution is pumped into 10000L reaction kettle, slowly opens collet steam valve, by mother liquor simple distillation, removes residue and salt；
Steam temperature in the kettle be 90 DEG C when, stop distillation, the distillate volume about 7920L steamed (for the 88% of total mother liquor volume)；
(2) distillate of step (1) is transferred in 10000L dehydrating kettle, detects distillate moisture, moisture 0.5vt% is left
The methanol solution 198.1kg for the sodium methoxide that mass percentage content is 30%, the second that mass percentage content is 20% is added in the right side
The ethanol solution 374.3kg (wherein, total Water molar ratio is 1:1 in the total amount and distillate of sodium methoxide and sodium ethoxide) of sodium alkoxide,
Reaction 12 minutes is stirred at room temperature；
(3) the ethyl acetate 193.8kg (total amount of ethyl acetate additional amount and sodium methoxide and sodium ethoxide is added into dehydrating kettle
Molar ratio be 1:1), be warming up to 50 ± 2 DEG C, react 2 hours；
(4) after reaction, quickly by the solvent air-distillation in dehydrating kettle, the amount of steaming is kettle internal solvent volume total amount
97%, vapo(u)rizing temperature is controlled at 90 ± 2 DEG C of temperature in the kettle, and White residule puts bucket in kettle, is sodium acetate；
(5) distillate is received, detection moisture is consistent for the ratio of 0.02vt%, methanol and proportion of ethanol and mother liquor component,
Preparation is crystallized for 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester to use.
Claims (6)
1. a kind of recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution, special
Sign is, comprising the following steps:
(1) by the mixed alcohol crystalline mother solution of the methanol of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester and ethyl alcohol,
Distillation, the distillate volume steamed are the 90 ± 2% of total mother liquor volume；
(2) distillate of step (1) is transferred to dehydrating kettle, detects distillate moisture, the methanol solution and/or second of sodium methoxide is added
The ethanol solution of sodium alkoxide reacts 10-15 minutes；
(3) ethyl acetate is added into dehydrating kettle, is warming up to 50 ± 2 DEG C, reacts 2 ± 1 hours；
(4) after reaction, air-distillation；
(5) distillate is received, moisture and content are detected, moisture control is 0.05vt% hereinafter, being used for 7- phenyl acetamide -3- chloromethane
Base cephalosporanic acid crystallizes preparation to methoxy benzyl ester and uses.
2. 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution according to claim 1 returns
Receive the method for utilizing, it is characterised in that: (2) in step, sodium methoxide mass percentage content is 5%- in the methanol solution of sodium methoxide
50%；Sodium ethoxide mass percentage content is 5%-50% in the ethanol solution of sodium ethoxide.
3. 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution according to claim 2 returns
Receive the method for utilizing, it is characterised in that: (2) in step, sodium methoxide mass percentage content is 30% in the methanol solution of sodium methoxide；
Sodium ethoxide mass percentage content is 20% in the ethanol solution of sodium ethoxide.
4. 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution according to claim 1 returns
Receive the method for utilizing, it is characterised in that: (2) in step, total Water molar ratio is in the amount and distillate of sodium methoxide and/or sodium ethoxide
Reaction 10-15 minutes is stirred at room temperature in 1:1.
5. 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution according to claim 1 returns
Receive the method for utilizing, it is characterised in that: (3) in step, ethyl acetate additional amount and sodium methoxide and/or sodium ethoxide molar ratio are 1:1.
6. 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution according to claim 1 returns
Receive the method for utilizing, it is characterised in that: (4) in step, the amount of steaming is the 95 ± 2% of kettle internal solvent volume total amount, vapo(u)rizing temperature control
System is at 90 ± 2 DEG C of temperature in the kettle.
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| CN201711408097.XA CN108047251B (en) | 2017-12-22 | 2017-12-22 | The recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution |
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| CN201711408097.XA CN108047251B (en) | 2017-12-22 | 2017-12-22 | The recoverying and utilizing method of 7-Phenylacetamide-3-chloromethylcephalosporanic acid-p-methoxybenzyl ester crystalline mother solution |
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| CN108047251B true CN108047251B (en) | 2019-11-19 |
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| CN102690243A (en) * | 2012-05-25 | 2012-09-26 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN105440053A (en) * | 2015-12-24 | 2016-03-30 | 湖北凌晟药业有限公司 | Method for recycling GCLE (7-phenylacetamido-3-chloromethylcephalosporanic acidp-methoxybenzyl ester) crystallization barren liquor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690243A (en) * | 2012-05-25 | 2012-09-26 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN105440053A (en) * | 2015-12-24 | 2016-03-30 | 湖北凌晟药业有限公司 | Method for recycling GCLE (7-phenylacetamido-3-chloromethylcephalosporanic acidp-methoxybenzyl ester) crystallization barren liquor |
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Denomination of invention: Recovery and utilization method of crystallization mother liquor of 7-phenylacetamide-3-chloromethylcephalosporin acid for methoxybenzyl ester Granted publication date: 20191119 Pledgee: Agricultural Bank of China Limited Xiangyang High tech Zone Branch Pledgor: Hubei Lingsheng Pharmaceutical Co.,Ltd. Registration number: Y2024980002009 |