CN107383066A - A kind of method of latamoxef acid deprotection base - Google Patents

A kind of method of latamoxef acid deprotection base Download PDF

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Publication number
CN107383066A
CN107383066A CN201710636686.7A CN201710636686A CN107383066A CN 107383066 A CN107383066 A CN 107383066A CN 201710636686 A CN201710636686 A CN 201710636686A CN 107383066 A CN107383066 A CN 107383066A
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China
Prior art keywords
compound
latamoxef
deprotection base
formula
acid deprotection
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Pending
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CN201710636686.7A
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Chinese (zh)
Inventor
王作弟
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Shanxi Qian Xiu Pharmaceutical Co Ltd
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Shanxi Qian Xiu Pharmaceutical Co Ltd
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Priority to CN201710636686.7A priority Critical patent/CN107383066A/en
Publication of CN107383066A publication Critical patent/CN107383066A/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/02—Preparation
    • C07D505/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention is by compound（I）First chlorination obtains compound in organic solvent（Ⅱ）, compound（Ⅱ）With compound（Ⅲ）Reaction generation compound（Ⅳ）, the last condensing crystallizing of washing purification obtains target compound after sloughing protection group again after washing purification（Ⅴ）.The product purity that the preparation method of the present invention obtains is high, and high income, color is good, the investment easy to operate for reducing equipment, and energy consumption is low.

Description

A kind of method of latamoxef acid deprotection base
Technical field
The invention belongs to deprotect base technical field, more particularly to a kind of method of latamoxef acid deprotection base.
Background technology
At present during latamoxef acid is prepared, the protection group for causing latamoxef acid without suitable method is gone Fall, cause the product purity that is prepared low, yield is low, complex operation, high energy consumption.
The content of the invention
It is a primary object of the present invention to, there is provided a kind of method of latamoxef acid deprotection base, technology to be solved Problem is to improve product purity, improves product purity.
The purpose of the present invention and technical problem to be solved are achieved through the following technical solutions.
A kind of method of latamoxef acid deprotection base, comprises the following steps：
Step 1：By compound（I）Chlorination obtains compound in organic solvent with chloride（Ⅱ）, wherein compound（I）'s Structure such as formula（I）It is shown
Compound（Ⅱ）Structure such as formula（Ⅱ）It is shown：
Step 2：The compound that step 1 obtains（Ⅱ）With compound（Ⅲ）Reaction generation compound（Ⅳ）, washing purification, wherein Compound（Ⅲ）Structural formula such as formula（Ⅲ）It is shown：
Compound（Ⅳ）Structural formula such as formula（Ⅳ）It is shown：
Step 3：The compound that step 2 obtains（Ⅳ）Enriching hydrochloric acid sloughs protection group, and then washing purification, is finally concentrated to give Target compound（Ⅴ）；
The wherein structural formula of compound V such as formula（Ⅴ）It is shown：
Preferably, the chloride used in step 1 is POCl3；Chlorination reaction temperature is 0~5 DEG C；POCl3 is with changing Compound（I）Mol ratio be 0.8~1:1.
Preferably, adding acid binding agent in step 2 course of reaction, the acid binding agent is organic base, and the organic base is three Ethamine or pyridine or sodium acetate.
Preferably, organic solvent used in step 1 is dichloromethane.
Preferably, the step 2 reaction temperature is 5~10 DEG C.
Washed preferably, the water-washing process of step 2 adds ketone with water formation mixed solvent, described ketone For at least one of acetone or butanone.
Preferably, water-washing process is washed with water in step 3, washing temperature is 10~15 DEG C.
Preferably, in step 3 concentration process be negative pressure concentration, thickening temperature be 20~25 DEG C, vacuum for- 0.08MPa。
The present invention is by compound（I）First chlorination obtains compound in organic solvent（Ⅱ）, compound（Ⅱ）With chemical combination Thing（Ⅲ）Reaction generation compound（Ⅳ）, the last condensing crystallizing of washing purification obtains after sloughing protection group again after washing purification Target compound（Ⅴ）.The product purity that the preparation method of the present invention obtains is high, and high income, color is good, easy to operate to reduce The investment of equipment, energy consumption are low.
Embodiment
With reference to specific embodiment, the present invention is further elaborated, and following examples will be helpful to the skill of this area Art personnel further understand the present invention, but it is only the better embodiment of the present invention, and the invention is not limited in any way.Therefore The equivalence changes that all features and principle according to described in present patent application scope are done, are included in present patent application model In enclosing.
Embodiment
A kind of method of latamoxef acid deprotection base, comprises the following steps：
Dichloromethane 600ml is put into there-necked flask, puts into compound（I）40g, input POCl3 14g, 5~10 DEG C of reactions Two hours, then put into compound（Ⅲ）24g, it is cooled to 0 DEG C of input acid binding agent 15ml.Water and acetone mixed solution are used after having reacted Abstraction impurity removal, merge organic phase, completely concentration, be cooled to 10 DEG C, input concentrated hydrochloric acid 14g, 10~15 DEG C of reaction 4h, put into acetic acid Ethyl ester 180g, ion, merge organic layer, completely concentration, the 300g crystallizations of input dichloromethane, filtering, baking material.
The present invention is by compound（I）First chlorination obtains compound in organic solvent（Ⅱ）, compound（Ⅱ）With chemical combination Thing（Ⅲ）Reaction generation compound（Ⅳ）, the last condensing crystallizing of washing purification obtains after sloughing protection group again after washing purification Target compound（Ⅴ）.The product purity that the preparation method of the present invention obtains is high, and high income, color is good, easy to operate to reduce The investment of equipment, energy consumption are low.

Claims (7)

  1. A kind of 1. method of latamoxef acid deprotection base, it is characterised in that comprise the following steps：
    Step 1：By compound（I）Chlorination obtains compound in organic solvent with chloride（Ⅱ）, wherein compound（I）'s Structure such as formula（I）It is shown
    Compound（Ⅱ）Structure such as formula（Ⅱ）It is shown：
    Step 2：The compound that step 1 obtains（Ⅱ）With compound（Ⅲ）Reaction generation compound（Ⅳ）, washing purification, wherein Compound（Ⅲ）Structural formula such as formula（Ⅲ）It is shown：
    Compound（Ⅳ）Structural formula such as formula（Ⅳ）It is shown：
    Step 3：The compound that step 2 obtains（Ⅳ）Enriching hydrochloric acid sloughs protection group, and then washing purification, is finally concentrated to give Target compound（Ⅴ）；
    The wherein structural formula of compound V such as formula（Ⅴ）It is shown：
    A kind of method of latamoxef acid deprotection base according to claim 1, it is characterised in that the chlorine used in step 1 Compound is POCl3；Chlorination reaction temperature is 0~5 DEG C；POCl3 and compound（I）Mol ratio be 0.8~1:1.
  2. 2. the method for a kind of latamoxef acid deprotection base according to claim 1, it is characterised in that step 2 was reacted Acid binding agent is added in journey, the acid binding agent is organic base, and the organic base is triethylamine or pyridine or sodium acetate.
  3. 3. the method for a kind of latamoxef acid deprotection base according to claim 1, it is characterised in that have used in step 1 Solvent is dichloromethane.
  4. 4. the method for a kind of latamoxef acid deprotection base according to claim 1, it is characterised in that the step 2 is anti- It is 5~10 DEG C to answer temperature.
  5. A kind of 5. method of latamoxef acid deprotection base according to claim 1, it is characterised in that the washing of step 2 Process adds ketone and washed with water formation mixed solvent, and described ketone is at least one of acetone or butanone.
  6. 6. the method for a kind of latamoxef acid deprotection base according to claim 1, it is characterised in that washed in step 3 Process water is washed, and washing temperature is 10~15 DEG C.
  7. 7. the method for a kind of latamoxef acid deprotection base according to claim 1, it is characterised in that concentrated in step 3 Process concentrates for negative pressure, and thickening temperature is 20~25 DEG C, and vacuum is -0.08MPa.
CN201710636686.7A 2017-07-31 2017-07-31 A kind of method of latamoxef acid deprotection base Pending CN107383066A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018233461A1 (en) * 2017-06-23 2018-12-27 浙江惠迪森药业有限公司 Method for removing carboxyl and hydroxy protective groups of latamoxef
CN110372728A (en) * 2019-08-14 2019-10-25 山西海泰电子材料有限公司 A kind of preparation method of oxacephem parent nucleus intermediate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1547351A (en) * 1976-03-25 1979-06-13 Shionogi & Co Arylmalonamido - 1 - oxadethiacephalosporins
US4203982A (en) * 1976-08-10 1980-05-20 Shionogi & Co., Ltd. Arylmalonamidomethoxycephalosporins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1547351A (en) * 1976-03-25 1979-06-13 Shionogi & Co Arylmalonamido - 1 - oxadethiacephalosporins
US4323567A (en) * 1976-03-25 1982-04-06 Masayuki Narisada Arylmalonamido-1-oxadethiacephalosporins
US4203982A (en) * 1976-08-10 1980-05-20 Shionogi & Co., Ltd. Arylmalonamidomethoxycephalosporins

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018233461A1 (en) * 2017-06-23 2018-12-27 浙江惠迪森药业有限公司 Method for removing carboxyl and hydroxy protective groups of latamoxef
CN110372728A (en) * 2019-08-14 2019-10-25 山西海泰电子材料有限公司 A kind of preparation method of oxacephem parent nucleus intermediate

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