CN107383083A - A kind of production method for improving organosilicon medicine intermediate BSA purity - Google Patents
A kind of production method for improving organosilicon medicine intermediate BSA purity Download PDFInfo
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- CN107383083A CN107383083A CN201710677090.1A CN201710677090A CN107383083A CN 107383083 A CN107383083 A CN 107383083A CN 201710677090 A CN201710677090 A CN 201710677090A CN 107383083 A CN107383083 A CN 107383083A
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- ethylchlorosilane
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 239000003814 drug Substances 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 claims description 89
- 230000015572 biosynthetic process Effects 0.000 claims description 84
- 239000007788 liquid Substances 0.000 claims description 41
- 239000005046 Chlorosilane Substances 0.000 claims 1
- YGZSVWMBUCGDCV-UHFFFAOYSA-N chloro(methyl)silane Chemical compound C[SiH2]Cl YGZSVWMBUCGDCV-UHFFFAOYSA-N 0.000 claims 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 80
- 238000006243 chemical reaction Methods 0.000 description 59
- 239000003039 volatile agent Substances 0.000 description 52
- 238000004821 distillation Methods 0.000 description 34
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 33
- 239000000463 material Substances 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 238000003860 storage Methods 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 19
- 239000007789 gas Substances 0.000 description 18
- 210000003128 head Anatomy 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 13
- 150000002460 imidazoles Chemical class 0.000 description 11
- 238000012856 packing Methods 0.000 description 10
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 238000007086 side reaction Methods 0.000 description 7
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 6
- 150000003869 acetamides Chemical class 0.000 description 6
- 230000001351 cycling effect Effects 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- -1 sulfidomethyl Chemical group 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000003223 protective agent Substances 0.000 description 4
- 230000036632 reaction speed Effects 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 229920000548 poly(silane) polymer Polymers 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VVAKEQGKZNKUSU-UHFFFAOYSA-N 2,3-dimethylaniline Chemical class CC1=CC=CC(N)=C1C VVAKEQGKZNKUSU-UHFFFAOYSA-N 0.000 description 1
- VOWZNBNDMFLQGM-UHFFFAOYSA-N 2,5-dimethylaniline Chemical class CC1=CC=C(C)C(N)=C1 VOWZNBNDMFLQGM-UHFFFAOYSA-N 0.000 description 1
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical class CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 1
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical class CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910000062 azane Inorganic materials 0.000 description 1
- AAMATCKFMHVIDO-UHFFFAOYSA-N azane;1h-pyrrole Chemical class N.C=1C=CNC=1 AAMATCKFMHVIDO-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- ACXMTAJLYQCRGF-PBFPGSCMSA-N cefatrizine Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC1=CN=N[N]1 ACXMTAJLYQCRGF-PBFPGSCMSA-N 0.000 description 1
- 229960002420 cefatrizine Drugs 0.000 description 1
- 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 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000013070 direct material Substances 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003027 ear inner Anatomy 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003961 organosilicon compounds Chemical class 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000000066 reactive distillation Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- FZGRPBJBMUNMQH-UHFFFAOYSA-N trimethyl-$l^{3}-chlorane Chemical compound CCl(C)C FZGRPBJBMUNMQH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
The present invention provides a kind of production method for improving organosilicon medicine intermediate BSA purity, methods described, including starts that trim,ethylchlorosilane, regulation trim,ethylchlorosilane rate of addition, temperature is added dropwise；The regulation trim,ethylchlorosilane rate of addition, temperature, control 33 39 DEG C of dropping temperature, and trim,ethylchlorosilane control added in 90 110 minutes.Finished product prepared by the present invention, purity are 99.51 99.62%, and once through yield is 91.33 93.66%.
Description
The present invention is application number 201510614597.3, the applying date：On September 24th, 2015, denomination of invention：" a kind of double groups
The divisional application of part catalyst synthesis N, the method for O-bis- (trimethylsilyl) acetamide ".
Technical field
The present invention relates to a kind of dual-component catalyst to synthesize N, the method for O-bis- (trimethylsilyl) acetamide, belongs to organic
Synthesis technical field.
Background technology
N, O-bis- (trimethylsilyls) acetamide (hereinafter referred to as BSA) are important organosilyl protective agents.Organosilicon is protected
Agent refers to be used for a kind of organic-silylation reagent for protecting various organo-functional groups in organic synthesis.In organic synthesis, if point
Several positions or functional group may react in son, if only wanting to react on a certain position or functional group, Er Qieyou
Selective reaction condition or reagent are can not find, the position that can now would not want to react protects, and waits and achieves the goal
Recover original functional group again afterwards.Organosilyl protective agents generally can be divided into trimethyl silicon type, simple function steric hindrance type, difunctionality position
Resistance type and the major class of Special type four.BSA is the most frequently used trimethyl silicon type protective agent, is mainly used in amino acid, completes acid, alcohol and acid amides
Silanization protection, be neutral silanes protective agent, have low toxicity, easily reaction, the property such as easily remove, in analytical chemistry, organic
Synthesis, medicine and natural substance modified etc. application are increasingly subject to pay attention to.
BSA products, for preparing cephalosporins medicine and its intermediate, such as synthesize cephalo as important medicine intermediate
Amino acid, synthesizing propanediol cefatrizine, the ammonia azoles sulfidomethyl cephalosporanic acid diformazan of synthesis 7- Α methoxyl group -7- amino -3- methyl four
Base ester, synthesis 7-7 α of beta-amino-methoxyl group-3- [（1- methyl isophthalic acid H- tetrazolium -5- bases）Sulfidomethyl] -3- cephem -4- carboxylic acids two
Benzene methyl etc.；Synthesis of selective cholesterol absorption inhibitor bulk drug ezetimibe；Passivation and sample as chromosorb
The modifying agent of polar group, a variety of compounds that qualitative and quantitative analysis can not be carried out using conventional chromatography evaluation are analyzed
Obtain satisfied result.In recent years with the rapid perfect, development of China's organosilicon chemistry technology, make organo-silicon compound conduct
The correlation research of pharmaceutical synthesis reagent and intermediate has obtained most attention.BSA is increasingly obtained extensively in organic synthesis
Using, particularly in compound structure containing unsaturated bond, hydroxyl, carbonyl, carboxyl, amino and the protection of other functional groups, BSA
Play and more importantly acted on.
Existing BSA synthetic methods mainly have：
Chinese patent（Application number：200410044929.0）BSA production technologies are proposed, its primary operational is：To anti-during synthesis
Kettle input triethylamine and acetamide are answered, is stirred 1 hour, then in N2Under the protection of gas, trimethyl chlorine is added dropwise into reactor
Silane, control temperature have filled in the range of 50 DEG C of ＜ in 2-6 hours, and then protection reaction is 8-16 small in 40-65 DEG C
When, reaction is cooled to less than 35 DEG C after terminating, discharging；The material reacted is added in closing centrifuge and carries out separation of solid and liquid,
Mother liquor send in concentration kettle and concentrated, and for the mother liquor after concentration at 60-100 DEG C, pressure is -0.2 to -0.998 atmospheric pressure, tower height
The colourless transparent liquid that rectifying obtains is carried out under the conditions of 6-15 rice.The main deficiency of the technique is：（1）Reaction time is grown, during reaction
Between more than 10 hours；(2) reaction is carried out at ambient pressure, although using N2The protection of gas, reaction system unavoidably enter sky
Gas simultaneously brings moisture into, it may occur that other side reactions；（3）Under the conditions of vacuum is 0.2 to 0.998 atmospheric pressure, tower height 6-15 rice
Rectifying is carried out, power consumption is big, high energy consumption, especially to reach the condition that vacuum is 0.998 atmospheric pressure, and power consumption is too big.
Chinese patent（Application number：200810120760.0）Propose be using TSIM and acetamide as raw material,
Using sulfhydryl compound as catalyst, pass through reactive distillation synthesis BSA method.In a band constant pressure funnel, thermometer, magnetic force
Stirring and with 33.6g (0.24mol) trimethyl silicon based imidazoles and 1.5g are added in 250 milliliters of there-necked flasks of 1 meter of rectifying column
(0.01mol) 2- mercaptobenzothiazolers, and by 12g (0.2mol) acetamides and 33.6g (0.24mol) trimethyl silicon substrate miaow
The mixed liquor of azoles is added to constant pressure funnel.Then heat, open magnetic agitation, depressurize, it is vacuum to control reaction pressure
Mixed liquor is slowly added dropwise from constant pressure funnel, side border ring rectifying, receives at 160 DEG C or so for 0.08MPa, control temperature of reaction kettle
The cut of less than 90 DEG C of collection is BSA crude products, and it is 5 hours to control the reaction time.Then, crude product is rectifying to obtain high content
BSA sterlings, yield 85%, content 99.2%.The main deficiency of the technique is：（1）Accessory substance acetonitrile and silicon ether are produced, and then
Some other side reaction can occur；（2）Reaction temperature is high, and temperature of reaction kettle is controlled at 160 DEG C or so, and power consumption is larger, easily causes
BSA loses；（3）Under the conditions of vacuum 0.08MPa, the reaction time is also up to 5 hours；（4）Production cost is high, to raw material
TSIM quality requirement is high.
French Patent (FRP)（The patent No.：FR2574079）Synthesis BSA route is proposed, this method is with the silicon of hexamethyl two
Azane is raw material, elder generation and acetic anhydride, then generates BSA with trim,ethylchlorosilane and triethylamine react.The technique is mainly insufficient
It is：（1）Although this reaction only produces the triethylamine hydrochloride of half amount in acetamide and trim,ethylchlorosilane reaction, it
The acetate of trimethyl silicone hydride, easily blocking pipeline are generated again, have a strong impact on that reaction is carried out；（2）Side reaction increase, by-product
Thing increases, and production cost is high；（3）Finished product purity is low, and amount of impurities and content are higher.
United States Patent (USP)（The patent No.:US4276423）Propose using trimethyl silicon based imidazole and N- trimethyl silicon substrate acetyl
The method that amine prepares BSA.Temperature of reaction system regulation vacuum 65mmHg posts, the distillation of side border ring, is reacted at 120-170 DEG C
Yield more than 90%.The main deficiency of the technique is：（1）Trimethyl silicon based imidazole can occur reversible with N- trimethyl silicanes yl acetamide
Reaction, reaction temperature are high；（2）Because side reaction is more, in product, amount of impurities is more, content is high：（3）Work is distilled using side border ring
Skill, industrialized production enforcement difficulty are big.
In recent years, with the research and development of the new cephalosporin analog antibiotic of the third generation and the success of Clinical practice, in pharmaceutical synthesis
To BSA purity requirement more and more highers, conventional purity 99.0 (GC) % can not meet to require；In addition, utilize MEMS (micro-electro-mechanical systems
Unite) purity 99.5 must be used in use for the MEMS cell captures chip for being used to separate and detect cancer cell of technical backstopping
(GC) more than % BSA, otherwise testing result is without in all senses；Other several injection cephalosporin analog antibiotic synthesis must make
With purity 99.5 (GC) more than % BSA, otherwise side reaction especially severe side reaction occurs even to occur again and again after human body injection
It is dead.Long reaction time, production cost height, product purity mostly be present on 99.0 (GC) % left sides in domestic and international existing BSA production technologies
The right side, product stability are poor（A period of time product is placed its colour changed into yellow occur, have floccule etc.）.Therefore, exploitation one kind carries simultaneously
High BSA purity and the production method of yield, to promoting industry development, there are important economic implications and social benefit.
The content of the invention
For reaction temperature is high, the reaction time is long, product purity low impurity content present in domestic existing BSA productions
It is high, improve yield and cost the problems such as raising, the present invention provides a kind of dual-component catalyst synthesis N, O-bis- (trimethylsilyl)
The method of acetamide, trim,ethylchlorosilane, triethylamine and the acetamide being easy to get using the country add other organic base conduct as raw material
Acid binding agent plays catalytic action simultaneously, is reacted under rough vacuum, with circulating pump forced circulation except promoting reaction to carry out
Outside, the hydrochloride for reacting generation is removed from reaction system in time, greatly accelerates reaction speed；Using smart under vacuum condition
Evaporate, product quality is stable and the holding time is grown.
The goal of the invention that the present invention realizes is：
（1）Shorten the reaction time；
（2）Reaction temperature is reduced, reaction temperature is reduced to less than 40 DEG C；
（3）Product BSA purity is brought up to more than 99.5% (GC)；
（4）Amount of impurities is reduced, impurity content is reduced, especially to reduce the labyrinths such as polysilane in product, polyoxy silane
Compound content；
（5）Reduce amine content in product；
（6）While improving yield, production cost is reduced；
（7）Product excellent storage stability.
The reaction principle of the present invention is as follows：
In BSA synthetic reactions, trim,ethylchlorosilane and acetamide are reacted as direct material, and triethylamine is as acid binding agent
To neutralize the HCl of trim,ethylchlorosilane and acetamide generation, medium is set to keep neutral or alkalescent, to improve the receipts of acylation reaction
Rate, reaction equation show as follows：
To solve above technical problem, the technical solution adopted by the present invention is as follows：
A kind of dual-component catalyst synthesizes N, the method for O-bis- (trimethylsilyl) acetamide, including trim,ethylchlorosilane charging, closes
Fed into kettle, regulation trim,ethylchlorosilane rate of addition, temperature, reaction.
It is the further improvement to above-mentioned technical proposal below：
The synthesis reactor charging, synthesis reactor is added by acetamide, triethylamine, catalyst dimethylaniline and catalyst imidazoles；Institute
It is 1 that acetamide, which is stated, with triethylamine weight ratio:3.60-3.94.
The catalyst dimethylaniline dosage is the 0.1-0.5% of acetamide weight.
The catalyst imidazoles dosage is the 0.08-0. 6% of acetamide weight.
The trim,ethylchlorosilane charging, the addition of trim,ethylchlorosilane and the weight ratio of acetamide are 3.77-4.03：
1。
The synthesis reactor charging, after raw material adds, starts to stir, and agitator speed is set as 85-100RPM, stirs 45-
After 55 minutes, adjustment synthesis reactor vacuum is 0.01-0.025MPa.
The regulation trim,ethylchlorosilane rate of addition, temperature, control 33-39 DEG C of dropping temperature, trim,ethylchlorosilane control
System adds within 90-110 minutes.
The reaction, trim,ethylchlorosilane are added dropwise, and it is 33-39 DEG C to continue to keep reaction temperature, keeps synthesis reactor true
Reciprocal of duty cycle is 0.01-0.025MPa, and circulating pump continues cycling through 120-150 minutes, and reaction terminates.
Finished product prepared by the present invention, purity 99.51-99.62%, once through yield 91.33-93.66%.
The present invention selects suitable catalyst, based on Lewis alkali, accelerates the reaction speed of trim,ethylchlorosilane and acetamide
Degree, makes acetamide carbonyl increased activity, so as to improve its reactivity；Reduce BSA and hydrogen chloride touch opportunity.
The present invention, while the triethylamine hydrochloride of generation is removed into reaction system, maintains essentially in reaction while reaction
Carried out under homogeneous phase condition, in time remove generation triethylamine hydrochloride, be also beneficial to accelerate reaction speed, reduce finished product BSA with
Hydrogen chloride deep reaction generates other compounds.
The selection of catalyst of the present invention, by test of many times, it is determined that the use of dimethylaniline is major catalyst, wherein 2,
6- dimethylanilines are other as 2,5- dimethylanilines, 3,4- dimethylanilines, 2,3- dimethylanilines also may be used preferably to use
Use；Meanwhile selected imidazoles is used as cocatalyst, imidazoles boiling point is higher, easy to divide with BSA boiling-point differences away from big when finished product separates
From.
Beneficial effects of the present invention are：
（1）In trim,ethylchlorosilane and acetamide synthetic reaction of the present invention using dual-component catalyst catalyst dimethylaniline with
Imidazoles, to be reacted under the conditions of low vacuum, reaction speed is accelerated,
Reaction time of the invention (finishes) from starting to be fed to reaction, is 4-4.5 hours, in the prior art industrialized producing technology
Generally 8-18 hours.
（2）Reaction temperature is reduced to as 33-39 DEG C by present 40-65 DEG C；Rectification temperature, receive finished product condensate temperature
73 DEG C are reduced to by 90 DEG C, significantly reduces other side reactions such as finished product BSA decomposition, polymerization.
（3）Product BSA prepared by the present invention, initially operate under vacuum during distillation, rear distillation uses Gao Zhen
Empty, low-temperature operation, product purity bring up to 99.51-99.62%.
（4）Product BSA prepared by the present invention, amount of impurities and impurity content are few, and polysilane, polyoxy silane etc. are multiple in product
Miscellaneous structural compounds content is low, controls polysilane content≤0.1%, polyoxy silane contents≤0.1% in product.
（5）In product prepared by the present invention, amine content is low, amine content 0.21-0.35%.
（6）The inventive method, while improving yield, production cost is reduced, BSA once through yield is domestic up to 93.66%
Existing yield is no more than 90%, and product cost reduces by more than 2%.
（7）Solves the problems, such as product bin stability difference；
Product prepared by the present invention, excellent storage stability, product purity is 99.40-99.53% (GC) after storing 1 year, and outward appearance is
Colourless transparent liquid, no floccule.Domestic like product bin stability is poor, and purity declines 3% after storing 1 year, and product is
It is micro- yellow to faint yellow, or even there is floccule.
（8）When trim,ethylchlorosilane being added dropwise into kettle, trim,ethylchlorosilane charge door is immersed in below synthesis reactor liquid level；Follow
The circulation fluid of ring pump must be immersed in below synthesis reactor liquid level into synthesis reactor circulation line charging aperture.Plus synthesis reactor in negative pressure
Under state, raw material trim,ethylchlorosilane hardly weakens significantly with air contact, moisture to the Hydrolysis of trim,ethylchlorosilane,
The conversion ratio of raw material trim,ethylchlorosilane is improved, conversion ratio improves more than 3%.
（9）Connection circulating pump is exported in reactor bottom, the i.e. open the circulation pump after starting to be added dropwise trim,ethylchlorosilane, with
Reactor agitator acts synergistically, and enhances the degree of material mixing, promotes heat and mass；Two filterings are followed by circulating pump
Device, one is used for coarse filtration（Filtering accuracy 100-200 mesh）, one is used to carefully filter（Filtering accuracy 300-400 mesh）, filter out life
Into triethylamine hydrochloride, system reacts under homogeneous phase condition, and material contact is more abundant, and reaction effect is good.
Brief description of the drawings
It is further described below in conjunction with the technological process of accompanying drawing and implementation to the present invention and equipment.
Fig. 1 is BSA synthesis technique schematic flow sheets；
In figure：1- trim,ethylchlorosilane head tanks；The pipelines of 2- first regard cup；3- synthesis reactors；4- circulating pumps；5- first filters；
The filters of 6- second；7- distillation stills；8- packed towers；9- condensers；10- front-end volatiles receiving tanks；11- finished product receiving tanks；12- waterpower
Ejector vacuum pump；13- oil seal type oil-sealed rotary pumps；14- first pressures（Vacuum）Site instructions device；The temperature of 15- first is just
Ground instruction device；16- second temperature site instructions devices；The pipelines of 17- second regard cup.18- second pressures（Vacuum）Refer on the spot
Showing device；The pressure of 19- the 3rd（Vacuum）Site instructions device.
Embodiment
The preferred embodiments of the present invention are illustrated below, it will be appreciated that preferred embodiment described herein is only used
In the description and interpretation present invention, it is not intended to limit the present invention.
A kind of 1 dual-component catalyst of embodiment synthesizes N, the method for O-bis- (trimethylsilyl) acetamide
Reaction is carried out in 1000L kettles, and synthesis step is as follows：
（1）Trim,ethylchlorosilane feeds
350kg trim,ethylchlorosilanes are extracted into trim,ethylchlorosilane head tank 1 with vacuum, start to keep trimethylchloro-silicane before feeding
The tiny structure of alkane head tank 1, keep vacuum 0.001-0.005
MPa。
（2）Synthesis reactor 3 feeds
By 90kg acetamides, 345kg triethylamines, 0.15kg2,6- dimethylanilines add synthesis reactor 3 with 0.25kg imidazoles, open
Stirring, agitator speed are set as 85RPM, and after stirring 45 minutes, the adjustment vacuum of synthesis reactor 3 is 0.01-0.015MPa.
（3）Start that trim,ethylchlorosilane is added dropwise
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in below the liquid level of synthesis reactor 3 at 20-35mm, start that trim,ethylchlorosilane i.e. open the circulation pump is added dropwise to synthesis reactor 3
4, material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, in first filter 5, the second mistake
The triethylamine hydrochloride of generation is filtered out in filter 6；Circulation fluid must be submerged in synthesis into the circulation line charging aperture of synthesis reactor 3
Below the liquid level of kettle 3 at 20-35mm.
（4）Adjust trim,ethylchlorosilane rate of addition, temperature
Trim,ethylchlorosilane rate of addition is adjusted, controls 33-35 DEG C of dropping temperature, trim,ethylchlorosilane control added in 90 minutes
It is complete.
（5）Reaction
Trim,ethylchlorosilane is added dropwise, and it is 33-35 DEG C to continue to keep reaction temperature, and it is 0.01- to keep the vacuum of synthesis reactor 3
0.015MPa, circulating pump 4 continue cycling through 120 minutes, and reaction terminates.
（6）Material is sent into distillation still 7
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7, open the circulation pump 4, by thing in synthesis reactor 3
Material is sent into distillation still 7 and distilled.
（7）Distill to obtain front-end volatiles
Destilling tower used in distillation is packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum reaches 0.082-0.086MPa, steam heating pot is passed through to the chuck of distillation still 3
Interior material, cup 17 is regarded by the second pipeline, material is examined and steams situation.Work as second pressure（Vacuum）Site instructions device
After the vacustat of 18 displays, before 68 DEG C（That is temperature<68℃）Condensate liquid accessed as front-end volatiles, and by front-end volatiles
In front-end volatiles receiving tank 10, the first front-end volatiles are obtained；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13；Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
The gas phase temperature situation of change of temperature site instructions device 16, it is 0.096~0.099MPa to keep vacuum and intercept vacuum, then
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10, obtains second
Front-end volatiles.
（8）Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close the valve of front-end volatiles receiving tank 10 and open the valve of finished product receiving tank 11
Door, 70.1-73 DEG C is intercepted, gained condensate liquid is as finished product and is linked into finished product receiving tank 11.
（9）Close Distallation systm, finished product packing storage, low temperature storage
Observed when the temperature rise for observing the display of second temperature site instructions device 16 and by the second pipeline regarding cup 17
When the condensation flow quantity come out from condenser 9 is reduced, first close distillation still 7 and heat steam, when observing that the second pipeline regards cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.
The BSA products of preparation, once through yield 91.33%, purity (GC) 99.51%.It is shown in Table 1
BSA product quality indicators made from table 1
Product purity is 99.42% (GC) after product is stored 1 year, and outward appearance is colourless transparent liquid, no floccule.
A kind of 2 dual-component catalyst of embodiment synthesizes N, the method for O-bis- (trimethylsilyl) acetamide
Reaction is carried out in 1000L kettles.Synthesis step is as follows：
（1）Trim,ethylchlorosilane feeds
380kg trim,ethylchlorosilanes are extracted into trim,ethylchlorosilane head tank 1 with vacuum, start to keep trimethylchloro-silicane before feeding
The tiny structure of alkane head tank 1, keep vacuum 0.001-0.005MPa.
（2）Synthesis reactor 3 feeds
By 100kg acetamides, 365kg triethylamines, 0.2kg2,6- dimethylanilines add synthesis reactor 3 with 0.2kg imidazoles, open
Stirring, agitator speed are set as 85RPM, and after stirring 50 minutes, the adjustment vacuum of synthesis reactor 3 is 0.01-0.015MPa.
（3）Start that trim,ethylchlorosilane is added dropwise
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below the liquid level of synthesis reactor 3；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into the circulation line charging aperture of synthesis reactor 3
20-35cm below 3 liquid levels.
（4）Adjust trim,ethylchlorosilane rate of addition, temperature
Trim,ethylchlorosilane rate of addition is adjusted, controls 33-35 DEG C of dropping temperature, trim,ethylchlorosilane was controlled in 100 minutes
Add.
（5）Reaction
Trim,ethylchlorosilane is added dropwise, and it is 33-35 DEG C to continue to keep reaction temperature, and it is 0.01- to keep the vacuum of synthesis reactor 3
0.015MPa, circulating pump 4 continue cycling through 130 minutes, and reaction terminates.
（6）Material is sent into distillation still 7
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7；Open the circulation pump 4, by thing in synthesis reactor 3
Material is sent into distillation still 7, and adds the front-end volatiles of embodiment 1.
（7）Distill to obtain front-end volatiles
Destilling tower used in distillation is packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum reaches 0.082-0.086MPa, steam heating pot is passed through to the chuck of distillation still 7
Interior material, material is examined depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum）Site instructions device
After the vacustat of 18 displays, before 68 DEG C of gained（<68℃）Condensate liquid as front-end volatiles, and evaporated before front-end volatiles are accessed
Tap in closed cans 10, obtain the first front-end volatiles；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
The gas phase temperature situation of change of temperature site instructions device 16, it is 0.096~0.099MPa to keep vacuum and intercept vacuum；Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10, obtains second
Front-end volatiles.
（8）Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close the valve of front-end volatiles receiving tank 10 and open the valve of finished product receiving tank 11
Door, 70.1-73 DEG C is intercepted, gained condensate liquid is as finished product and is linked into finished product receiving tank 11.
（9）Close Distallation systm, finished product packing storage, low temperature storage
Observed when the temperature rise for observing the display of second temperature site instructions device 16 and by the second pipeline regarding cup 17
When the condensation flow quantity come out from condenser 9 is reduced, first close distillation still 7 and heat steam, when observing that the second pipeline regards cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.The product of preparation：Once through yield 92.46%, purity (GC) 99.55%.It is shown in Table 2
Product quality indicator made from table 2
Product purity is 99.43% (GC) after product is stored 1 year, and outward appearance is colourless transparent liquid, no floccule.
A kind of 3 dual-component catalyst of embodiment synthesizes N, the method for O-bis- (trimethylsilyl) acetamide
Reaction is carried out in 1000L kettles, and synthesis step is as follows：
（1）Trim,ethylchlorosilane feeds
420kg trim,ethylchlorosilanes are extracted into trim,ethylchlorosilane head tank 1 with vacuum, start to keep trimethylchloro-silicane before feeding
The tiny structure of alkane head tank 1, keep vacuum 0.001-0.005MPa.
（2）Synthesis reactor 3 feeds
By 110kg acetamides, 400kg triethylamines, 0.3kg2,6- dimethylanilines add synthesis reactor 3 with 0.2kg imidazoles, open
Stirring, agitator speed are set as 90RPM.After stirring 50 minutes, the adjustment vacuum of synthesis reactor 3 is 0.01-0.015MPa.
（3）Start that trim,ethylchlorosilane is added dropwise
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure.Trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below the liquid level of synthesis reactor 3；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into the circulation line charging aperture of synthesis reactor 3
20-35cm below 3 liquid levels.
（4）Adjust trim,ethylchlorosilane rate of addition, temperature
Trim,ethylchlorosilane rate of addition is adjusted, controls 33-35 DEG C of dropping temperature, trim,ethylchlorosilane was controlled in 100 minutes
Add.
（5）Reaction
Trim,ethylchlorosilane is added dropwise, and it is 33-35 DEG C to continue to keep reaction temperature, and it is 0.01- to keep the vacuum of synthesis reactor 3
0.015MPa, circulating pump 4 continue cycling through 130 minutes, and reaction terminates.
（6）Material is sent into distillation still
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7, open the circulation pump 4, by thing in synthesis reactor 3
Material is sent into distillation still 7, and adds the front-end volatiles of embodiment 2.
（7）Distill to obtain front-end volatiles
Destilling tower used in distillation is packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum reaches 0.082-0.086MPa, steam heating pot is passed through to the chuck of distillation still 7
Interior material, material is examined depending on cup 17 by the second pipeline and steams situation；Work as second pressure（Vacuum）Site instructions device
After the vacustat of 18 displays, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and evaporated before front-end volatiles are accessed
Tap in closed cans 10, obtain the first front-end volatiles；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
The gas phase temperature situation of change of temperature site instructions device 16, it is 0.096~0.099MPa to keep vacuum and intercept vacuum；Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10, obtains second
Front-end volatiles.
（8）Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close the valve of front-end volatiles receiving tank 10 and open the valve of finished product receiving tank 11
Door, 70.1-73 DEG C is intercepted, gained condensate liquid is as finished product and is linked into finished product receiving tank 11.
（9）Close Distallation systm, finished product packing storage, low temperature storage
Observed when the temperature rise for observing the display of second temperature site instructions device 16 and by the second pipeline regarding cup 17
When the condensation flow quantity come out from condenser 9 is reduced, first close distillation still 7 and heat steam, when observing that the second pipeline regards cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.The product of preparation, once through yield 92.96%, purity (GC) 99.52%.It is shown in Table 3
Product quality indicator made from table 3
Product purity is 99.40% (GC) after product is stored 1 year, and outward appearance is colourless transparent liquid, no floccule.
A kind of 4 dual-component catalyst of embodiment synthesizes N, the method for O-bis- (trimethylsilyl) acetamide
Reaction is carried out in 1000L kettles, and synthesis step is as follows：
（1）Trim,ethylchlorosilane feeds
460kg trim,ethylchlorosilanes are extracted into trim,ethylchlorosilane head tank 1 with vacuum, start to keep trimethylchloro-silicane before feeding
The tiny structure of alkane head tank 1, keep vacuum 0.001-0.005MPa.
（2）Synthesis reactor 3 feeds
By 120kg acetamides, 440kg triethylamines, 0.3kg2,6- dimethylanilines add synthesis reactor 3 with 0.3kg imidazoles, open
Stirring, agitator speed are set as 90RPM.After stirring 50 minutes, the adjustment vacuum of synthesis reactor 3 is 0.015-0.02MPa.
（3）Start that trim,ethylchlorosilane is added dropwise
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure.Trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below the liquid level of synthesis reactor 3；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into the circulation line charging aperture of synthesis reactor 3
20-35cm below 3 liquid levels.
（4）Adjust trim,ethylchlorosilane rate of addition, temperature
Trim,ethylchlorosilane rate of addition is adjusted, controls 36-39 DEG C of dropping temperature, trim,ethylchlorosilane was controlled in 110 minutes
Add.
（5）Reaction
Trim,ethylchlorosilane is added dropwise, and it is 36-39 DEG C to continue to keep reaction temperature, and it is 0.015- to keep the vacuum of synthesis reactor 3
0.02MPa, circulating pump 4 continue cycling through 150 minutes, and reaction terminates.
（6）Material is sent into distillation still 7
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7.Open the circulation pump 4, by thing in synthesis reactor 3
Material is sent into distillation still 7, and adds the front-end volatiles of embodiment 3.
（7）Distill to obtain front-end volatiles
Destilling tower used in distillation is packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum reaches 0.082-0.086MPa, steam heating pot is passed through to the chuck of distillation still 7
Interior material, material is examined depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum）Site instructions device
After the vacustat of 18 displays, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and evaporated before front-end volatiles are accessed
Tap in closed cans 10；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
The gas phase temperature situation of change of temperature site instructions device 16, it is 0.096~0.099MPa to keep vacuum and intercept vacuum.Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10.
（8）Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close the valve of front-end volatiles receiving tank 10 and open the valve of finished product receiving tank 11
Door, gained condensate liquid intercept 70.1-73 DEG C, as finished product and are linked into finished product receiving tank 11.
（9）Close Distallation systm, finished product packing storage, low temperature storage
Observed when the temperature rise for observing the display of second temperature site instructions device 16 and by the second pipeline regarding cup 17
When the condensation flow quantity come out from condenser 9 is reduced, first close distillation still 7 and heat steam, when observing that the second pipeline regards cup 17
When liquid is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature is deposited under the conditions of nitrogen-sealed
Storage.The product of preparation, once through yield 93.28%, purity (GC) 99.60%.It is shown in Table 4
Product quality indicator made from table 4
Product purity is 99.50% (GC) after product is stored 1 year, and outward appearance is colourless transparent liquid, no floccule.
A kind of 5 dual-component catalyst of embodiment synthesizes N, the method for O-bis- (trimethylsilyl) acetamide
Reaction is carried out in 1000L kettles, and synthesis step is as follows：
（1）Trim,ethylchlorosilane feeds
470kg trim,ethylchlorosilanes are extracted into trim,ethylchlorosilane head tank 1 with vacuum, start to keep trimethylchloro-silicane before feeding
The tiny structure of alkane head tank 1, keep vacuum 0.001-0.005MPa.
（2）Synthesis reactor 3 feeds
By 120kg acetamides, 460kg triethylamines, 0.45kg2,6- dimethylanilines add synthesis reactor 3 with 0.4kg imidazoles, opened
Stirring is opened, agitator speed is set as 100RPM.After stirring 55 minutes, the adjustment vacuum of synthesis reactor 3 is 0.02-0.025MPa.
（3）Start that trim,ethylchlorosilane is added dropwise
Trim,ethylchlorosilane head tank 1 is adjusted to normal pressure, trim,ethylchlorosilane, trim,ethylchlorosilane charge door are added dropwise into kettle
It must be submerged in 20-35cm below the liquid level of synthesis reactor 3；Start that trim,ethylchlorosilane i.e. open the circulation pump 4 is added dropwise to synthesis reactor 3,
Material enters synthesis reactor 3 by circulating pump 4, first filter 5, the second filter 6 successively, is filtered in first filter 5, second
The triethylamine hydrochloride of generation is filtered out in device 6；Circulation fluid must be submerged in synthesis reactor into the circulation line charging aperture of synthesis reactor 3
20-35cm below 3 liquid levels.
（4）Adjust trim,ethylchlorosilane rate of addition, temperature
Trim,ethylchlorosilane rate of addition is adjusted, controls 36-39 DEG C of dropping temperature, trim,ethylchlorosilane was controlled in 110 minutes
Add.
（5）Reaction
Trim,ethylchlorosilane is added dropwise, and it is 36-39 DEG C to continue to keep reaction temperature, and it is 0.02- to keep the vacuum of synthesis reactor 3
0.025MPa, circulating pump 4 continue cycling through 150 minutes, and reaction terminates.
（6）Material is sent into distillation still 7
The material valve for leading to synthesis reactor 3 is closed, opens the valve for leading to distillation still 7.Open the circulation pump 4, by synthesis reactor 3
Material is sent into distillation still 7, and adds the front-end volatiles of embodiment 4.
（7）Distill to obtain front-end volatiles
Destilling tower used in distillation is packed tower 8,4 meters of tower height, built-in tetrafluoro filler.
A, the collection of the first front-end volatiles
Hydraulic jet pump 12 is first opened, when vacuum reaches 0.082-0.086MPa, steam heating pot is passed through to the chuck of distillation still 7
Interior material, material is examined depending on cup 17 by the second pipeline and steams situation.Work as second pressure（Vacuum）Site instructions device
After the vacustat of 18 displays, before 68 DEG C of gained condensate liquid（<68℃）Be used as front-end volatiles, and evaporated before front-end volatiles are accessed
Tap in closed cans 10；
B, the collection of the second front-end volatiles
When gas phase temperature is stepped up to 68.1 DEG C, first steam off valve, then switch vacuum system, by water-jet vacuum
Pump 12 is switched to oil seal type oil-sealed rotary pump 13.Oil seal type oil-sealed rotary pump 13 is stable, after vacustat, observation second
The gas phase temperature situation of change of temperature site instructions device 16, it is 0.096~0.099MPa to keep vacuum and intercept vacuum.Again
After secondary unlatching steam valve, the condensate liquid of 68.1-70 DEG C of gained is also served as in front-end volatiles access front-end volatiles receiving tank 10.
（8）Distill to obtain finished product
When gas phase temperature is stepped up to 70.1 DEG C, close the valve of front-end volatiles receiving tank 10 and open the valve of finished product receiving tank 11
Door, gained condensate liquid intercept 70.1-73 DEG C, as finished product and are linked into finished product receiving tank 11.
（9）Close Distallation systm, finished product packing storage, low temperature storage
Observed when the temperature rise for observing the display of second temperature site instructions device 16 and by the second pipeline regarding cup 17
When the condensation flow quantity come out from condenser 9 is reduced, first close distillation still 7 and heat steam, when observing that the second pipeline regards cup liquid
When body is almost without dropping down, oil seal type oil-sealed rotary pump 13 is closed, finished product packing storage, low temperature stores under the conditions of nitrogen-sealed.
The product prepared, once through yield 93.66%, purity (GC) 99.62%.It is shown in Table 5
Product quality indicator made from table 5
Product purity is 99.53% (GC) after product is stored 1 year, and outward appearance is colourless transparent liquid, no floccule.
Unless otherwise indicated, the percentage employed in the present invention is percetage by weight, ratio of the present invention,
For mass ratio.
Finally it should be noted that：The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention,
Although the present invention is described in detail with reference to the foregoing embodiments, for those skilled in the art, it still may be used
To be modified to the technical scheme described in foregoing embodiments, or equivalent substitution is carried out to which part technical characteristic.
Within the spirit and principles of the invention, any modification, equivalent substitution and improvements made etc., it should be included in the present invention's
Within protection domain.
Claims (2)
- A kind of 1. production method for improving organosilicon medicine intermediate BSA purity, it is characterised in that：Methods described, including start Trim,ethylchlorosilane, regulation trim,ethylchlorosilane rate of addition, temperature is added dropwise；The regulation trim,ethylchlorosilane rate of addition, temperature, control 33-39 DEG C of dropping temperature, and trim,ethylchlorosilane control exists 90-110 is added in minute.
- 2. a kind of production method for improving organosilicon medicine intermediate BSA purity according to claim 1, its feature exist In：It is described to start that trim,ethylchlorosilane is added dropwise, trim,ethylchlorosilane head tank is adjusted to normal pressure, trimethyl is added dropwise into kettle Chlorosilane, trim,ethylchlorosilane charge door must be submerged in below synthesis reactor liquid level at 20-35mm, start to be added dropwise three to synthesis reactor Methylchlorosilane is open the circulation pump.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710677090.1A CN107383083A (en) | 2015-09-24 | 2015-09-24 | A kind of production method for improving organosilicon medicine intermediate BSA purity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510614597.3A CN105131026B (en) | 2015-09-24 | 2015-09-24 | A kind of dual-component catalyst synthesizes N, the method for O-bis- (trimethylsilyl) acetamide |
| CN201710677090.1A CN107383083A (en) | 2015-09-24 | 2015-09-24 | A kind of production method for improving organosilicon medicine intermediate BSA purity |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510614597.3A Division CN105131026B (en) | 2015-09-24 | 2015-09-24 | A kind of dual-component catalyst synthesizes N, the method for O-bis- (trimethylsilyl) acetamide |
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| Publication Number | Publication Date |
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| CN107383083A true CN107383083A (en) | 2017-11-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710677090.1A Withdrawn CN107383083A (en) | 2015-09-24 | 2015-09-24 | A kind of production method for improving organosilicon medicine intermediate BSA purity |
| CN201510614597.3A Expired - Fee Related CN105131026B (en) | 2015-09-24 | 2015-09-24 | A kind of dual-component catalyst synthesizes N, the method for O-bis- (trimethylsilyl) acetamide |
| CN201710675934.9A Withdrawn CN107365325A (en) | 2015-09-24 | 2015-09-24 | A kind of purity is high, the production method of the N of high income, O-bis- (trimethylsilyls) acetamide |
| CN201710677089.9A Withdrawn CN107383082A (en) | 2015-09-24 | 2015-09-24 | A kind of composite catalyzing produces high purity N, the method for O-bis- (trimethylsilyl) acetamide |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510614597.3A Expired - Fee Related CN105131026B (en) | 2015-09-24 | 2015-09-24 | A kind of dual-component catalyst synthesizes N, the method for O-bis- (trimethylsilyl) acetamide |
| CN201710675934.9A Withdrawn CN107365325A (en) | 2015-09-24 | 2015-09-24 | A kind of purity is high, the production method of the N of high income, O-bis- (trimethylsilyls) acetamide |
| CN201710677089.9A Withdrawn CN107383082A (en) | 2015-09-24 | 2015-09-24 | A kind of composite catalyzing produces high purity N, the method for O-bis- (trimethylsilyl) acetamide |
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| CN (4) | CN107383083A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1699308A (en) * | 2004-05-20 | 2005-11-23 | 孙友璋 | Process for preparing N,O-bis(trimethylsilyl)acetamide |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1793307U (en) * | 1959-04-30 | 1959-08-13 | Georg Westphal | DEVICE FOR MALT CRUSHING. |
| DE19807021C1 (en) * | 1998-02-19 | 1999-02-11 | Wacker Chemie Gmbh | Preparation of N-tri:organo-silyl carboxamide(s) |
| FR2807041B1 (en) * | 2000-03-29 | 2002-11-29 | Atofina | SEMI-CONTINUOUS PROCESS FOR THE PREPARATION OF BIS-SILYL CARBOXYLIC ACID AMIDES |
| CN1699375A (en) * | 2004-05-20 | 2005-11-23 | 孙友璋 | Process for preparing N,O-bis tri silicyl trifluoroacetamide |
-
2015
- 2015-09-24 CN CN201710677090.1A patent/CN107383083A/en not_active Withdrawn
- 2015-09-24 CN CN201510614597.3A patent/CN105131026B/en not_active Expired - Fee Related
- 2015-09-24 CN CN201710675934.9A patent/CN107365325A/en not_active Withdrawn
- 2015-09-24 CN CN201710677089.9A patent/CN107383082A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1699308A (en) * | 2004-05-20 | 2005-11-23 | 孙友璋 | Process for preparing N,O-bis(trimethylsilyl)acetamide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105131026B (en) | 2017-10-03 |
| CN105131026A (en) | 2015-12-09 |
| CN107383082A (en) | 2017-11-24 |
| CN107365325A (en) | 2017-11-21 |
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Application publication date: 20171124 |