CN108905264A - Application and continuous crystallization system of the continuous crystallization method in beta-lactam antibiotic synthesis - Google Patents
Application and continuous crystallization system of the continuous crystallization method in beta-lactam antibiotic synthesis Download PDFInfo
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- CN108905264A CN108905264A CN201810783988.1A CN201810783988A CN108905264A CN 108905264 A CN108905264 A CN 108905264A CN 201810783988 A CN201810783988 A CN 201810783988A CN 108905264 A CN108905264 A CN 108905264A
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 252
- 230000008025 crystallization Effects 0.000 title claims abstract description 243
- 239000003782 beta lactam antibiotic agent Substances 0.000 title claims abstract description 20
- 239000002132 β-lactam antibiotic Substances 0.000 title claims abstract description 19
- 229940124586 β-lactam antibiotics Drugs 0.000 title claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract description 109
- 238000006243 chemical reaction Methods 0.000 claims abstract description 105
- 238000000034 method Methods 0.000 claims abstract description 50
- 239000013078 crystal Substances 0.000 claims abstract description 49
- 230000008569 process Effects 0.000 claims abstract description 39
- 239000002904 solvent Substances 0.000 claims description 93
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 230000001105 regulatory effect Effects 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 230000009471 action Effects 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 238000005185 salting out Methods 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 9
- 230000003115 biocidal effect Effects 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- FWRNIJIOFYDBES-ZQDFAFASSA-L disodium;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfonatoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].[Na+].C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)S([O-])(=O)=O)=CC=CC=C1 FWRNIJIOFYDBES-ZQDFAFASSA-L 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- GRIXGZQULWMCLU-HUTAOCTPSA-L disodium;(6r,7r)-7-[[2-carboxylato-2-(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C([O-])=O)=O)C(=O)C(C([O-])=O)C1=CC=C(O)C=C1 GRIXGZQULWMCLU-HUTAOCTPSA-L 0.000 claims description 4
- 229960000433 latamoxef Drugs 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000003068 static effect Effects 0.000 claims description 4
- 230000007246 mechanism Effects 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 229960002793 amoxicillin sodium Drugs 0.000 claims description 2
- ILVPFTMKCHREDJ-UHFFFAOYSA-N methyl 5-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1F ILVPFTMKCHREDJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- -1 methyl tertbutyl Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 13
- 238000004090 dissolution Methods 0.000 abstract description 8
- 239000012296 anti-solvent Substances 0.000 abstract description 6
- 230000014759 maintenance of location Effects 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 150000003952 β-lactams Chemical class 0.000 description 4
- 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 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010924 continuous production Methods 0.000 description 3
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 2
- 229960004920 amoxicillin trihydrate Drugs 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 241000208340 Araliaceae Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000244 anti-pseudomonal effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 229960004489 cefonicid Drugs 0.000 description 1
- NAXFZVGOZUWLEP-RFXDPDBWSA-L cefonicid sodium Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)[C@H](O)C=2C=CC=CC=2)CC=1CSC1=NN=NN1CS([O-])(=O)=O NAXFZVGOZUWLEP-RFXDPDBWSA-L 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 150000002961 penems Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/62—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
-
- 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
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application and continuous crystallization system that the present invention provides a kind of continuous crystallization methods in beta-lactam antibiotic synthesis.The continuous crystallization system includes：Multiple crystallization reaction units of setting are sequentially connected in series, carry out continuous crystallization for making material to be crystallized continue through each crystallization reaction unit.When being crystallized using above-mentioned continuous crystallization system, in entire production process, the technological parameters such as degree of dissolution saturation, crystallization retention time, the feed way of anti-solvent and mixed effect can be consistent, so as to improve the homogeneity of crystal product.Using continuous crystallization system carry out crystallization can also cost process reduce, while the production capacity flexibility ratio with higher for the appliance arrangement being related in above-mentioned continuous crystallization system can adapt to the production of different scales requirement.
Description
Technical field
The present invention relates to beta-lactam antibiotic synthesis field, in particular to a kind of continuous crystallization method in β-
Application and continuous crystallization system in lactam antibiotics synthesis.
Background technique
Beta-lactam antibiotic means the major class antibiotic in chemical structure with beta-lactam nucleus, including blueness
Mycin and its derivative, cephalosporin, monoamides ring class, carbapenem and penems enzyme inhibitor etc. and the head of new development
Other atypia beta-lactam antibiotics such as mycin class, thiomycin class, monobactams.It is essentially all in its molecule
Antibiotic in structure including beta-lactam core belongs to beta-lactam class antibiotic.Such antibiotic has bactericidal activity strong, malicious
The low, wide indications of property and the good advantage of clinical efficacy, are most popular one kind in existing antibiotic.
Crystallization process is generally used for the separation and purifying of product material, due to the raw material in pharmaceuticals industry, more than 90%
Medicine (API) is the organic compound molecule of crystal habit, thus crystallization process is the important ring that can influence properties of product
Section.The technique of crystallization process can effectively control the property such as size, shape, particle diameter distribution, yield, purity and crystal form of product crystal
Matter.Firstly, the quality control of crystal product will have a direct impact on the physico-chemical property (such as rate of dissolution, solubility etc.) of product；Together
When, the purifying of crystal product and yield optimization need to meet purity requirement and production capacity；In addition, the quality of crystal product controls
Also the technological effect of downstream process (such as filtering, dry and grinding) will further be influenced.Therefore, in the industrial production, in order to
Meet the quality requirement of crystal product and the global optimization of technical process, when the degree of dissolution saturation, crystallization in crystallization process retain
Between, the technological parameters such as the feed way of anti-solvent and mixed effect require to control effectively.Knot in industrial production at present
Brilliant process is all based on the batch processes of anti-solvent crystallization, the processes such as crystallization or crystal seed crystallization that cool down.In order to meet extensive life
The product demand of production needs to carry out multiple batch crystallization.It is degree of dissolution saturation, crystallization retention time, anti-due in crystallization process
The kinds of processes such as feed way and mixed effect of solvent parameter will all directly affect product quality, the weight between different production batch
Renaturation is more difficult to control.
Summary of the invention
The main purpose of the present invention is to provide a kind of continuous crystallization methods to synthesize in beta-lactam antibiotic
In application and continuous crystallization system, to solve the granularity uniformity of crystal product existing for existing batch method for crystallising
Poor problem.
To achieve the goals above, it provides according to an aspect of the present invention a kind of suitable for beta-lactam antibiotic conjunction
At continuous crystallization system, continuous crystallization system includes：Be sequentially connected in series multiple crystallization reaction units of setting, for make to
The material of crystallization continues through each crystallization reaction unit and carries out continuous crystallization.
Further, continuous crystallization system includes the first crystallization reaction unit and the second crystallization reaction unit.First knot
Brilliant reaction member is provided with the first feed opening, the second feed opening and first discharge port, and the first feed opening is used for object to be crystallized
Material is continuously delivered in the first crystallization reaction unit, and first discharge port is for continuously arranging the first material after crystallization
Out；Second crystallization reaction unit is provided with third feed opening, the 4th feed opening and the second discharge gate, third feed opening and first row
Material mouth is connected by the first transfer pipeline, for first material continuously being inputted in the second crystallization reaction device, the second discharge
Second material of the mouth for that will crystallize through the second crystallization reaction unit is discharged.
Further, continuous crystallization system further includes the first solvent supply unit, with without interruption for to be crystallized
Material carry out antisolvent crystallisation the first solvent, and the first solvent supply unit respectively with the second feed opening and/or the 4th plus
Material mouth is connected.
Further, the first crystallization reaction unit includes the first crystallization reaction device and the first temperature regulating device.First crystallization
Reaction unit is provided with the first feed opening, the second feed opening and first discharge port；First temperature regulating device is for adjusting the first crystallization
Temperature in reaction unit.
Further, the second crystallization reaction unit includes：Second crystallization reaction device and the second temperature regulating device, the second crystallization
Reaction unit is provided with third feed opening, the 4th feed opening and the second discharge gate；Second temperature regulating device is for adjusting the second crystallization
Temperature in reaction unit.
Further, continuous crystallization system further includes the second solvent supply unit, with without interruption for dissolving wait tie
Second solvent of brilliant material, and the second solvent supply unit is connected with the second feed opening.
Further, continuous crystallization system further includes the first conveying device, and the setting of the first conveying device is in the first conveying
On pipeline.
Further, the first conveying device is vacuum material transfer device or nitrogen material transferring device.
Further, the first crystallization reaction device and the second crystallization reaction device are separately selected from mixing discharge crystallization
Reactor or static mixer.
Further, the cooling temperature in the first crystallization reaction device is higher than the cooling temperature in the second crystallization reaction device
Degree.
Further, material to be crystallized is beta-lactam antibiotic sodium salt, is preferably selected from Amoxicillin Sodium, draws oxygen
Cefonicid sodium or sulbenicillin sodium.
On the other hand the application additionally provides a kind of application of continuous crystallization method in beta-lactam antibiotic synthesis,
The method of continuous crystallization includes that material to be crystallized is continuously carried out multiple crystallization treatment, and continuously outputting material obtains
Crystallized product.
Further, multiple crystallization includes：Second solvent and material to be crystallized are mixed, obtain first
Mixed liquor；First mixed liquor is continuously carried out to multiple decrease temperature crystalline processing, obtains crystallized product.
Further, multiple crystallization further includes：Second solvent, crystal seed and material to be crystallized are mixed,
Obtain the first mixed liquor.
Further, each time in decrease temperature crystalline treatment process, the temperature of the first mixed liquor is down to 0 DEG C by 70 DEG C, always
The crystallization time is 1~2h.
Further, multiple crystallization includes：Second solvent and material to be crystallized are mixed, obtain second
Mixed liquor；Under the action of the first solvent, so that the second mixed liquor is carried out continuously multiple antisolvent crystallisation processing, obtain crystallization and produce
Object；Preferably, total crystallization time of multiple antisolvent crystallisation treatment process is 1~2h.
Further, in terms of 100g material to be crystallized, the dosage of the second solvent is 50~300mL；Preferably, the second solvent
Selected from tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl acetate, methyl tertiary butyl ether(MTBE), cyclopentyl methyl ether, methanol, ethyl alcohol,
One of group of isopropanol, methylene chloride, toluene, acetonitrile, chloroform and acetone composition is a variety of.
Further, in terms of 100g material to be crystallized, the dosage of the second solvent is 500~1500mL；Preferably, first is molten
Agent is in the group that normal heptane, n-hexane, methyl tertiary butyl ether(MTBE), cyclopentyl methyl ether, methanol, ethyl alcohol, isopropyl alcohol and water form
It is one or more.
It applies the technical scheme of the present invention, when being crystallized using above-mentioned continuous crystallization system, in entire production process,
The technological parameters such as degree of dissolution saturation, crystallization retention time, the feed way of anti-solvent and mixed effect can be consistent, from
And it can be improved the homogeneity of crystal product.Simultaneously using continuous crystallization system carry out crystallization can also cost process reduce,
The production capacity flexibility ratio with higher for the appliance arrangement being related in above-mentioned continuous crystallization system simultaneously, can adapt to not
With the production of scale requirements.With easy to operate, equipment is sharp when furthermore being crystallized using above-mentioned continuous crystallization system
While reduction with rate height and production cost, additionally it is possible to effectively improve the processing capacity for treating crystallized stock.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present invention, and of the invention shows
Examples and descriptions thereof are used to explain the present invention for meaning property, does not constitute improper limitations of the present invention.In the accompanying drawings：
Fig. 1 shows the schematic diagram for the continuous crystallization system that a kind of typical embodiment according to the present invention provides；
Fig. 2 shows the schematic diagrames of the continuous crystallization system provided according to a preferred embodiment of the present invention；
Fig. 3 shows the signal for the continuous crystallization system that another preferred embodiment according to the present invention provides
Figure.
Wherein, above-mentioned attached drawing includes the following drawings label：
10, the first crystallization reaction unit；11, the first crystallization reaction device；12, the first temperature regulating device；13, material to be crystallized
Feeding mechanism；14, raw materials pump；
20, the second crystallization reaction unit；21, the second crystallization reaction device；22, the second temperature regulating device；
30, the first conveying device；
40, the first solvent supply unit；41, the first solvent charge pump；50, the second solvent supply unit；51, the second solvent
Charge pump.
Specific embodiment
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
As described in background technique, there are the granularity uniformity of crystal product is poor for existing batch method for crystallising
The problem of.In order to solve the above-mentioned technical problem, this application provides a kind of suitable for beta-lactam antibiotic synthesis process
Continuous crystallization system, the continuous crystallization system include：Multiple crystallization reaction units of setting are sequentially connected in series, for making wait tie
Brilliant material continues through each crystallization reaction unit and carries out continuous crystallization.
When being crystallized using above-mentioned continuous crystallization system, in entire production process, when degree of dissolution saturation, crystallization retain
Between, the technological parameters such as the feed way of anti-solvent and mixed effect can be consistent, so as to improve crystal product
Homogeneity.Process costs, while above-mentioned continuous crystallization system can also be reduced by carrying out crystallization using continuous crystallization system simultaneously
The production capacity for the appliance arrangement being related in system flexibility ratio with higher, the product that can adapt to different scales requirement are raw
It produces.Have easy to operate, utilization rate of equipment and installations high when furthermore being crystallized using above-mentioned continuous crystallization system and production cost drop
While low, additionally it is possible to effectively improve the processing capacity for treating crystallized stock.
In beta-lactam antibiotic synthesis process, as long as the step of involving the need for crystallization, can mention in the application
It is carried out in the continuous crystallization system of confession, material to be crystallized can be to need to crystallize in beta-lactam antibiotic synthesis process
Intermediate product or raw material and final product etc..
Preferably, as shown in Figure 1, the continuous crystallization system includes the first crystallization reaction unit 10 and the second crystallization reaction
Unit 20, the first crystallization reaction unit 10 are provided with the first feed opening, the second feed opening and first discharge port, and the first feed opening is used
In material to be crystallized to be continuously delivered in the first crystallization reaction unit 10, first discharge port is for continuously will be by crystallization
First material discharge afterwards；The second crystallization reaction unit 20 is provided with third feed opening, the 4th feed opening and the second discharge
Mouthful, third feed opening is connected with first discharge port by the first transfer pipeline, for first material continuously to be inputted to the second knot
In brilliant reaction unit 21, the second material that the second discharge gate is used to crystallize through the second crystallization reaction unit 20 is discharged.
In a preferred embodiment, above-mentioned continuous crystallization system further includes the first solvent supply unit 40, with
It is without interruption for carrying out the first solvent of antisolvent crystallisation to material to be crystallized, and the first solvent supply unit 40 respectively with
Second feed opening and/or the 4th feed opening are connected.
In above-mentioned continuous crystallization system, material to be crystallized is continuously inputted into the first crystallization reaction list through the first feed opening
In member 10, the first solvent is continuously inputted in the first crystallization reaction unit 10 or by the first solvent through the second feed opening through the 4th
Feed opening continuously inputs in the second crystallization reaction unit 20.Simultaneously in material to be crystallized and the first solvent in the second crystallization reaction
The antisolvent crystallisation process of serialization is carried out in unit 20, and the material obtained after crystallization is continuously discharged.
Structure in first crystallization reaction unit 10 and the second crystallization reaction unit 20 can be arbitrarily arranged, as long as it can
Realize the function of crystallization.In a preferred embodiment, the first crystallization reaction unit 10 includes：First crystallization reaction
Device 11 and the first temperature regulating device 12.First crystallization reaction device 11 is provided with the first feed opening, the second feed opening and first row
Material mouth；First temperature regulating device 12 is for adjusting temperature in the first crystallization reaction device 11.
In a preferred embodiment, the second crystallization reaction unit 20 includes：Second crystallization reaction device 21 and
Two temperature regulating devices 22.Second crystallization reaction device 21 is provided with third feed opening, the 4th feed opening and the second discharge gate；Second control
Warm device 22 is for adjusting temperature in the second crystallization reaction device 21.
When the first crystallization reaction unit 10 and the second crystallization reaction 20 above structure of unit, above-mentioned continuous reaction system
It can not only be crystallized using antisolvent crystallisation method, lowering temperature crystallization can also be used to be crystallized.Using lowering temperature crystallization
When being crystallized, the cooling temperature in the first crystallization reaction device 11 is higher than the cooling temperature in the second crystallization reaction device 21.
In a preferred embodiment, above-mentioned continuous crystallization system further includes the second solvent supply unit 50, with
It is without interruption to pass through the second solvent for dissolving the second solvent of material to be crystallized, the second solvent supply mouth and the second feed opening
Supply line is connected.It is highly preferred that above-mentioned continuous crystallization system further includes the second solvent charge pump 51, the charging of the second solvent
Pump 51 is arranged on the second solvent delivery pipeline.
It should be noted that during above-mentioned continuous crystallization, the second solvent can be replaced with crystal seed or crystal seed with
The mixture of second solvent.
In order to improve in the first transfer pipeline between the flow rate of first material, in a preferred embodiment,
Above-mentioned continuous crystallization system further includes the first conveying device 30, and the first conveying device 30 is arranged on the first transfer pipeline.
Preferably, include liquid level sensor in the first conveying device 30, liquid can be shifted by automatic control control system
Amount is precisely controlled and is monitored, and has super liquid level defencive function.
In a kind of preferred embodiment, as shown in Figure 1, under the action of raw materials pump 14, by material to be crystallized
It is continuously discharged from material supplying device 13 to be crystallized, and is continuously delivered to the first crystallization reaction device 11 through the first feed opening
In.Under the action of the first solvent charge pump 41, the first solvent that the first solvent supply unit 40 is provided is through the second feed opening
It is continuously delivered in the first crystallization reaction device 11.Under the action of the first temperature regulating device 12, by material to be crystallized and
One solvent carries out being mixed to get first material in the first crystallization reaction device 11, and first material is continuously discharged.By first
First material is continuously input in the second crystallization reaction device 21, in the second temperature regulating device by transfer pipeline through third feed opening
Continuous crystallization is carried out under the action of 22, obtains second material, and second material is continuously discharged.
In another preferred embodiment, as shown in Fig. 2, under the action of raw materials pump 14, by object to be crystallized
Material is continuously discharged from material supplying device 13 to be crystallized.Through the first feed opening, material to be crystallized is continuously input to first
In crystallization reaction device 11, under acting on by the first temperature regulating device 21, first material is obtained.In the effect of the first conveying device 30
Under, first material is continuously inputted in the second crystallization reaction device 21.It is molten by first under the action of the first solvent charge pump 41
What agent feeding mechanism 40 provided the first solvent is continuously discharged, and fills its second crystallization reaction of continuous input through the 4th feed opening
It sets in 21.Under the action of the second temperature regulating device 22, make material and the first solvent to be crystallized in the second crystallization reaction device 21
Middle progress continuous crystallization reaction, obtains required crystalline product.
In a kind of preferred embodiment, as shown in figure 3, under the action of raw materials pump 14, by material to be crystallized
It is continuously discharged from material supplying device 13 to be crystallized.The first crystallization reaction device is continuously delivered to through the first feed opening
In 11.Under the action of the second solvent charge pump 51, the second solvent or crystal seed are continuously delivered to the first crystallization reaction device
In 11.Under the action of the first temperature regulating device 12, material to be crystallized and the second solvent are mixed, obtain first material and by the
One material is continuously discharged.Under the action of the first conveying device 30, by first material through third feed opening, by the first transfer pipeline
Continuously it is input in the second crystallization reaction device 21.Under the action of the first solvent charge pump 41, by the first solvent supply unit
First solvent is continuously discharged for 40 offers.And it is continuously input in the second crystallization reaction device 21 through the 4th feed opening.
Under the action of the second temperature regulating device 22, continuous crystallization is carried out, obtains required crystal product, and it is continuously discharged.
Preferably, above-mentioned first solvent include but is not limited to normal heptane, n-hexane, methyl tertiary butyl ether(MTBE), cyclopentyl methyl ether,
One of group of methanol, ethyl alcohol, isopropyl alcohol and water composition is a variety of.Above-mentioned second solvent include but is not limited to tetrahydrofuran,
Ethyl acetate, isopropyl acetate, methyl acetate, methyl tertiary butyl ether(MTBE), cyclopentyl methyl ether, methanol, ethyl alcohol, isopropanol, dichloromethane
One of group of alkane, toluene, acetonitrile, chloroform and acetone composition is a variety of.By means of the first solvent and the second solvent to crystal
Impurity dissolubility it is different (i.e. anti-solvent crystallization method), thus further improve crystal product homogeneity and product can
Repeatability.
It is highly preferred that the first conveying device 30 is vacuum material transfer device.Using vacuum material transfer device as
In one conveying device 30, be conducive to completely cut off the influence to crystalline product such as empty gas and water, to be conducive to further increase final obtain
The stability and homogeneity of the crystal product arrived.
Preferably, the first crystallization reaction device 11 and the second crystallization reaction device 21 are separately selected from mixing discharge knot
Brilliant reactor or static mixer.In continuous crystallization system, made using mixing discharge crystallization reactor or static mixer
For crystallization reaction, it can be obviously improved the mixed effect of material, so as to inhibit the product grain generated by mixed effect difference
Degree is unevenly distributed first-class quality problem.Good material mixed effect also can further promote the yield of crystallization process to improve.
In a preferred embodiment, the cooling temperature in the first crystallization reaction device 11 is lower than the second crystallization reaction
Cooling temperature in device 21.Cooling temperature in first crystallization reaction device 11 is lower than cold in the second crystallization reaction device 21
But temperature is conducive to further improve the purity and homogeneity in crystal product by the crystallization method that cools down.
Since during pharmaceutical synthesis, the homogeneity of medicine intermediate has biggish shadow to the performance of drug target
It rings, thus needs to purify it by the way of crystallization.Preferably, using above-mentioned continuous crystallization system to beta-lactam
The medicine intermediate of class antibiotic synthesis process carries out crystallization process, such as beta-lactam antibiotic sodium salt, more preferably Ah not
XiLin sodium (semi-synthetic penicillins wide spectrum beta-lactam antibiotic), Latamoxef Sodium (semi-synthetic cephalosporins medicine β-interior
Amides antibiotic) or sulbenicillin sodium (the semi-synthetic anti-pseudomonad penicillin of wide spectrum).
On the other hand the application additionally provides a kind of application of continuous crystallization method in beta-lactam antibiotic synthesis,
The method of continuous crystallization includes that material to be crystallized is continuously carried out multiple crystallization treatment, and continuously outputting material obtains
Crystallized product.
In beta-lactam antibiotic synthesis, crystallized stock is treated using continuous crystallization processing mode and is crystallized
When, in entire production process, the techniques such as degree of dissolution saturation, crystallization retention time, the feed way of anti-solvent and mixed effect ginseng
Number can be consistent, so as to improve the homogeneity of crystal product, while can also by the way of continuous crystallization
Reduce process costs.
Each crystallization process can use crystallization treatment mode commonly used in the art, such as decrease temperature crystalline, seeded crystallization or anti-
Solvent crystallization.
In a preferred embodiment, above-mentioned multiple crystallization includes：By the second solvent and object to be crystallized
Material is mixed, and the first mixed liquor is obtained；First mixed liquor is continuously carried out to multiple decrease temperature crystalline processing, crystallization is obtained and produces
Object.
Preferably, above-mentioned multiple crystallization further includes：Second solvent, crystal seed and material to be crystallized are mixed
It closes, obtains the first mixed liquor.The precipitation efficiency for being conducive to improve crystal by the way that crystal seed is added, to be conducive to further increase drop
The precipitation efficiency of crystal in warm crystallization process.
In above-mentioned decrease temperature crystalline treatment process, temperature, the crystallization time, solvent dosage can use model commonly used in the art
It encloses.In a preferred embodiment, each time in decrease temperature crystalline treatment process, the temperature of the first mixed liquor is dropped by 70 DEG C
To 0 DEG C, total crystallization time is 1~2h.In decrease temperature crystalline treatment process, on cool down range and total crystallization time includes but is not limited to
Range is stated, and is limited the yield and homogeneity for being conducive to further increase crystal within the above range.
In above-mentioned decrease temperature crystalline treatment process, for the second solvent for dissolving material to be crystallized, the second solvent can
To select the conventional amount used of this field.Preferably, in terms of 100g material to be crystallized, the dosage of the second solvent is 1mL/g.By second
The dosage of solvent limits the degree of saturation for being conducive to improve the first mixed liquor within the above range, and then is conducive to improve crystal
Eduction rate.
Preferably, the second solvent includes but is not limited to tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl acetate, methyl
In the group that tertbutyl ether, cyclopentyl methyl ether, methanol, ethyl alcohol, isopropanol, methylene chloride, toluene, acetonitrile, chloroform and acetone form
It is one or more.
In another preferred embodiment, multiple crystallization includes：By the second solvent and material to be crystallized
It is mixed, obtains the second mixed liquor；Under the action of the first solvent, the second mixed liquor is made to be carried out continuously multiple antisolvent crystallisation
Processing, obtains crystallized product.
Preferably, total crystallization time of multiple antisolvent crystallisation treatment process is 1~2h.In decrease temperature crystalline treatment process,
Total crystallization time includes but is not limited to above range, and is limited the receipts for being conducive to further increase crystal within the above range
Rate and homogeneity.
In above-mentioned antisolvent crystallisation treatment process, the second solvent is for dissolving material to be crystallized, the second solvent
It can choose the conventional amount used of this field.Preferably, in terms of 100g material to be crystallized, the dosage of the second solvent is 50~300mL.
The dosage of second solvent is limited to the degree of saturation for being conducive to improve the first mixed liquor within the above range, and then is conducive to improve
Crystal yield.
Preferably, the second solvent includes but is not limited to tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl acetate, methyl
In the group that tertbutyl ether, cyclopentyl methyl ether, methanol, ethyl alcohol, isopropanol, methylene chloride, toluene, acetonitrile, chloroform and acetone form
It is one or more.
In above-mentioned antisolvent crystallisation treatment process, the difference of target product solubility in the first solvent and the second solvent,
The target product in the second mixed liquor is precipitated, the first solvent can choose the conventional amount used of this field.In a kind of preferred reality
It applies in mode, in terms of 100g material to be crystallized, the dosage of the first solvent is 500~1500mL.The dosage of first solvent is limited
Be conducive to improve the crystal eduction rate from the second mixed liquor within the above range, to improve the yield of crystal.
Preferably, the first solvent includes but is not limited to normal heptane, n-hexane, methyl tertiary butyl ether(MTBE), cyclopentyl methyl ether, first
One of group of alcohol, ethyl alcohol, isopropyl alcohol and water composition is a variety of.First solvent includes but is not limited to above-mentioned several, and is selected
Above-mentioned several substances are conducive to improve the solubility of target product in material to be crystallized as the first solvent, and then are conducive to improve
The yield of target product.
Preferably, the second solvent, crystal seed and the material to be crystallized are mixed, obtains second mixed liquor.It is logical
It crosses and the precipitation efficiency that crystal seed is conducive to crystal during raising antisolvent crystallisation is added, to be conducive to further increase crystal
Precipitation efficiency.
It should be noted that above-mentioned anti-solvent Crystallization Process, crystal seed Crystallization Process and cooling Crystallization Process can carry out group
It closes and uses, to further increase the yield of crystal.
The application is described in further detail below in conjunction with specific embodiment, these embodiments should not be understood as limitation originally
Apply for range claimed.
Embodiment 1
Material solution is obtained as shown in Figure 1,100g sulbenicillin sodium is dissolved in the first solvent (methanol, 300mL), then will
This solution and the second solvent of 6mL/g (acetone) are continuously delivered in the first crystallization reaction device 11.In the first temperature regulating device 12
Under the action of, so that the temperature of first material is risen to 60 DEG C, obtains first material, and first material is continuously discharged.
By first material through third feed opening, continuously it is input in the second crystallization reaction device 21 by the first transfer pipeline,
Under the action of the second temperature regulating device 22, first material is made to carry out continuous crystallization at 0~10 DEG C, obtains second material, and
Second material is continuously discharged.In above-mentioned continuous process, crystallization time 2h.The yield of crystal is 95wt%, homogeneity coefficient
It is 3.53.
Comparative example 1
100g sulbenicillin sodium is dissolved in the first solvent of 3mL/g (methanol) and obtains material solution, then into above-mentioned solution
6mL/g acetone is added dropwise.Gained system is first warming up to 60 DEG C, after keeping the temperature 1h, slow cooling is to 0~10 DEG C, 1~3h of crystallization.It is brilliant
Body yield 95wt%, homogeneity coefficient 4.21.
Embodiment 2
As shown in Fig. 2, 100g raw material Latamoxef Sodium is dissolved in the first solvent (methanol, 300mL), then by acquired solution
It is continuously delivered in the first crystallization reaction device 11, and its temperature is risen to 60 DEG C, obtains first material, and by first material
Continuous discharge.
By first material through third feed opening, continuously it is input in the second crystallization reaction device 21 by the first transfer pipeline,
And the second solvent of volume (methyl tertiary butyl ether(MTBE), 800mL) is continuously input to the second crystallization reaction device 21 through the 4th feed opening
In, continuous crystallization is carried out under the action of the second temperature regulating device, obtains second material, and second material is continuously discharged.On
It states in continuous process, crystallization retening temperature is 0 DEG C, crystallization time 2h.The yield of crystal is 85wt%, and homogeneity coefficient is
2.66。
Comparative example 2
100g Latamoxef Sodium is dissolved in the first solvent (methanol, 300mL), then 8mL/g methyl is added dropwise into above-mentioned solution
Tertbutyl ether.Gained system is first warming up to 60 DEG C, after keeping the temperature 1h, slow cooling is to 0~10 DEG C, 1~3h of crystallization.Crystal yield
85wt%, homogeneity coefficient 4.05.
Embodiment 3
As shown in figure 3,100g Amoxicillin trihydrate to be dissolved in the mixed solution of ethyl alcohol (300g) Yu triethylamine (250g)
In, and acquired solution is continuously delivered in the first crystallization reaction device 11, by sodium iso-octoate (40g) and methyl acetate
The mixed solution of (250g) is continuously delivered in the first crystallization reaction device 11, obtains first material, and first material is connected
Continuous discharge.
By first material through third feed opening, continuously it is input in the second crystallization reaction device 21 by the first transfer pipeline,
And be continuously input to aqueous sodium carbonate in the second crystallization reaction device 21 through the 4th feed opening, in the work of the second temperature regulating device
Continuous crystallization is carried out under, obtains second material, and second material is continuously discharged.In above-mentioned continuous process, crystallization is protected
Staying temperature is 0 DEG C, crystallization time 2h.The yield of crystal is 91wt%, homogeneity coefficient 2.95.
Comparative example 3
100g Amoxicillin trihydrate is dissolved in the mixed solution of ethyl alcohol (300g) and triethylamine (250g), then to above-mentioned
The mixed solution of sodium iso-octoate (40g) and methyl acetate (250g) are added dropwise in material, then is cooled to 0~5 DEG C, sodium carbonate is added dropwise
Solution, carries out batch crystallization, and crystallization retention time is 4h.The yield of crystal is 90wt%, homogeneity coefficient 3.46.
It can be seen from the above description that the above embodiments of the present invention realize following technical effect：
When being crystallized using above-mentioned continuous crystallization system, in entire production process, when degree of dissolution saturation, crystallization retain
Between, the technological parameters such as the feed way of anti-solvent and mixed effect can be consistent, so as to improve crystal product
Homogeneity.Simultaneously using continuous crystallization system carry out crystallization can also cost process reduce, while above-mentioned continuous crystallization system
The production capacity for the appliance arrangement being related in system flexibility ratio with higher, the product that can adapt to different scales requirement are raw
It produces.Have easy to operate, utilization rate of equipment and installations high when furthermore being crystallized using above-mentioned continuous crystallization system and production cost drop
While low, additionally it is possible to effectively improve the processing capacity for treating crystallized stock.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (18)
1. a kind of continuous crystallization system suitable for beta-lactam antibiotic synthesis process, which is characterized in that described continuous
Changing crystal system includes：Multiple crystallization reaction units of setting are sequentially connected in series, for making material to be crystallized continue through each institute
It states crystallization reaction unit and carries out continuous crystallization.
2. continuous crystallization system according to claim 1, which is characterized in that the continuous crystallization system includes：
First crystallization reaction unit (10), the first crystallization reaction unit (10) are provided with the first feed opening, the second feed opening
And first discharge port, first feed opening are used to material to be crystallized being continuously delivered to the first crystallization reaction unit
(10) in, the first discharge port is for continuously the first material after crystallization to be discharged；
Second crystallization reaction unit (20), the second crystallization reaction unit (20) are provided with third feed opening, the 4th feed opening
With the second discharge gate, the third feed opening is connected with the first discharge port by the first transfer pipeline, and being used for will be described
First material continuously inputs in the second crystallization reaction device (21), and second discharge gate through described second for that will crystallize
The second material discharge of reaction member (20) crystallization.
3. continuous crystallization system according to claim 2, which is characterized in that the continuous crystallization system further includes
One solvent supply unit (40), with without interruption for carrying out the first solvent of antisolvent crystallisation to the material to be crystallized,
And first solvent supply unit (40) is connected with second feed opening and/or the 4th feed opening respectively.
4. continuous crystallization system according to claim 2 or 3, which is characterized in that the first crystallization reaction unit
(10) include：
First crystallization reaction device (11), the first crystallization reaction device (11) are provided with first feed opening, described
Two feed openings and the first discharge port；
First temperature regulating device (12), first temperature regulating device (12) is for adjusting the first crystallization reaction device (11) medium temperature
Degree.
5. continuous crystallization system according to claim 4, which is characterized in that the second crystallization reaction unit (20) packet
It includes：
Second crystallization reaction device (21), the second crystallization reaction device (21) are provided with the third feed opening, described
Four feed openings and second discharge gate；
Second temperature regulating device (22), second temperature regulating device (22) is for adjusting the second crystallization reaction device (21) medium temperature
Degree.
6. continuous crystallization system according to claim 5, which is characterized in that the continuous crystallization system further includes
Two solvent supply units (50), with without interruption for dissolving the second solvent of the material to be crystallized, and it is described second molten
Agent feeding mechanism (50) is connected with second feed opening.
7. continuous crystallization system according to claim 2, which is characterized in that the continuous crystallization system further includes
One conveying device (30), first conveying device (30) are arranged on first transfer pipeline.
8. continuous crystallization system according to claim 7, which is characterized in that first conveying device (30) is vacuum
Material transferring device or nitrogen material transferring device.
9. continuous crystallization system according to claim 5, which is characterized in that the first crystallization reaction device (11) and
The second crystallization reaction device (21) is separately selected from mixing discharge crystallization reactor or static mixer.
10. continuous crystallization system according to claim 5, which is characterized in that the first crystallization reaction device (11)
In cooling temperature be higher than the second crystallization reaction device (21) in cooling temperature.
11. continuous crystallization system according to claim 1, which is characterized in that the material to be crystallized is the interior acyl of β-
Amine antibiotic sodium salt, is preferably selected from Amoxicillin Sodium, Latamoxef Sodium or sulbenicillin sodium.
12. a kind of application of continuous crystallization method in beta-lactam antibiotic synthesis, which is characterized in that the serialization knot
Brilliant method includes that material to be crystallized is continuously carried out multiple crystallization treatment, and continuously outputting material obtains crystallized product.
13. application according to claim 12, which is characterized in that the multiple crystallization includes：
Second solvent and the material to be crystallized are mixed, the first mixed liquor is obtained；
First mixed liquor is continuously subjected to multiple decrease temperature crystalline processing, obtains the crystallized product.
14. application according to claim 13, it is characterised in that：The multiple crystallization further includes：By first
Solvent, crystal seed and the material to be crystallized are mixed, and first mixed liquor is obtained.
15. application described in 3 or 14 according to claim 1, which is characterized in that each time in the decrease temperature crystalline treatment process,
The temperature of first mixed liquor is down to 0 DEG C by 70 DEG C, total crystallization time is 1~2h.
16. application according to claim 12, which is characterized in that the multiple crystallization includes：
Second solvent and the material to be crystallized are mixed, the second mixed liquor is obtained；
Under the action of the first solvent, so that second mixed liquor is carried out continuously multiple antisolvent crystallisation processing, obtain the knot
Brilliant product；
Preferably, total crystallization time of the multiple antisolvent crystallisation treatment process is 1~2h；
Preferably, the second solvent, crystal seed and the material to be crystallized are mixed, obtains second mixed liquor.
17. application described in 3 or 16 according to claim 1, which is characterized in that in terms of material to be crystallized described in 100g, described
The dosage of two solvents is 50~300mL；
Preferably, second solvent is selected from tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl acetate, methyl tertbutyl
One of ether, cyclopentyl methyl ether, methanol, ethyl alcohol, isopropanol, methylene chloride, toluene, acetonitrile, chloroform and group of acetone composition
Or it is a variety of.
18. application according to claim 16, which is characterized in that in terms of material to be crystallized described in 100g, described first is molten
The dosage of agent is 500~1500mL；
Preferably, first solvent is selected from normal heptane, n-hexane, methyl tertiary butyl ether(MTBE), cyclopentyl methyl ether, methanol, ethyl alcohol, different
One of group of third alcohol and water composition is a variety of.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627794A (en) * | 2019-10-15 | 2019-12-31 | 凯莱英医药集团（天津）股份有限公司 | Continuous post-treatment method and device for penem compounds |
| CN111518119A (en) * | 2020-05-26 | 2020-08-11 | 联邦制药(内蒙古)有限公司 | Continuous amoxicillin crystallization process |
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| CN113717114A (en) * | 2021-09-23 | 2021-11-30 | 济南悟通生物科技有限公司 | 2-acetylpyrazine continuous recrystallization device, method and application thereof |
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| CN110627794A (en) * | 2019-10-15 | 2019-12-31 | 凯莱英医药集团（天津）股份有限公司 | Continuous post-treatment method and device for penem compounds |
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| CN111518119A (en) * | 2020-05-26 | 2020-08-11 | 联邦制药(内蒙古)有限公司 | Continuous amoxicillin crystallization process |
| CN111804267A (en) * | 2020-07-10 | 2020-10-23 | 凯莱英医药化学（阜新）技术有限公司 | Continuous reaction equipment and application thereof |
| CN113717114A (en) * | 2021-09-23 | 2021-11-30 | 济南悟通生物科技有限公司 | 2-acetylpyrazine continuous recrystallization device, method and application thereof |
| CN113717114B (en) * | 2021-09-23 | 2022-12-02 | 济南悟通生物科技有限公司 | 2-acetylpyrazine continuous recrystallization device, method and application thereof |
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