CN110105253A - Application of the serialization micro passage reaction in pharmaceutical synthesis - Google Patents
Application of the serialization micro passage reaction in pharmaceutical synthesis Download PDFInfo
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- CN110105253A CN110105253A CN201810100499.1A CN201810100499A CN110105253A CN 110105253 A CN110105253 A CN 110105253A CN 201810100499 A CN201810100499 A CN 201810100499A CN 110105253 A CN110105253 A CN 110105253A
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- serialization
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 81
- 230000015572 biosynthetic process Effects 0.000 title abstract description 8
- 238000003786 synthesis reaction Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 18
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- -1 sulfonyl azide compound Chemical class 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 235000010288 sodium nitrite Nutrition 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000012549 training Methods 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 150000002170 ethers Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims 1
- 239000003205 fragrance Substances 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000003541 multi-stage reaction Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000002156 mixing Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 239000002699 waste material Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000935 solvent evaporation Methods 0.000 description 3
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- CBEPRWSVUHYMLI-UHFFFAOYSA-N dichloromethane;azide Chemical compound [N-]=[N+]=[N-].ClCCl CBEPRWSVUHYMLI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000010129 solution processing Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- NBINSWOYIKLKGL-UHFFFAOYSA-N 2-dodecylbenzenesulfonyl chloride Chemical compound CCCCCCCCCCCCC1=CC=CC=C1S(Cl)(=O)=O NBINSWOYIKLKGL-UHFFFAOYSA-N 0.000 description 1
- GYOBZOBUOMDRRN-UHFFFAOYSA-N 2-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=CC=C1S(Cl)(=O)=O GYOBZOBUOMDRRN-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MTEQRUUCSZTCHS-UHFFFAOYSA-N [S].NN Chemical compound [S].NN MTEQRUUCSZTCHS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- 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
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides application of the serialization micro passage reaction in pharmaceutical synthesis, more particularly to more reaction serializations of serialization micro passage reaction.The serialization more reacted has the characteristics of continuous output of the multistep reaction continuous feed of more significant ground, successive reaction and product, has the advantage of safe and environment-friendly and suitable industrialization.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to application of the serialization micro passage reaction in pharmaceutical synthesis,
The characteristics of can be realized the continuous output of multistep reaction continuous feed, successive reaction and product has safe and environment-friendly and is suitble to produce
The advantage of industry.
Background technique
Micro passage reaction is in periodical literature the 5th phase chemical industry progress of volume 23 " microreactor research and prospect " in 2004
In, the superiority for having big reactor incomparable in chemistry and chemical field by report microreactor shows temperature control,
Reactor volume, conversion ratio and yield guarantee safety, be easy to amplify etc..
Also, in periodical literature chemical progress 2008 the 1st phases " micro passage reaction answering in synthetic reaction of volume 20
With " page 67 common gas-liquid-solid multinomial catalysis is defined as to the hydrogenation of organic compound and is reacted.In urging for cyclohexene
Change the cross channel microreactor intersected in hydrogenation reaction using long and short two channel.It is catalysed and reduced into aniline in nitrobenzene
Gas-liquid-solid reaction is carried out using 64 parallel channels.But by further studying, think in the periodical literature,
Proper mode is that catalyst is fixed on to channel surface, has bigger contact area between such reactant, more
It is suitble to the phase reaction in microchannel to ketone, alkene, diene, alkynes etc..
Summarize in addition, the periodical literature has carried out experimental result to hydrogenation,
In Chinese granted patent CN103694169B, 2,2,4- trimethyl -1,2- dihydros are prepared using micro passage reaction
Quinoline and its polymer, Chinese patent application CN105566120A prepare isooctyl ester nitrate using micro passage reaction, and China is specially
Aniline diazotising is prepared phenylhydrazine using micro passage reaction by benefit application CN106316879A.
However, above-mentioned react the relatively conventional one-step reaction that is related to using micro passage reaction, current research and development are existing
Shape is also confined in the microchannel level of one-step reaction, thus, from angle prepared by final pharmaceutical synthesis and industrialized production
Degree sets out, it is necessary to which developing one whole should prepare final raw material from starting material or in which mesosome multistep serialization microchannel plate
One precursor reactant of serialization of medicine finally successfully realizes the theory and most of application of the serialization micro passage reaction in pharmaceutical synthesis
The good target for reaching industrialized production with this special kind of skill.
Summary of the invention
The present invention provides a kind of application of serialization micro passage reaction in pharmaceutical synthesis, can be realized multistep reaction
The characteristics of continuous output of continuous feed, successive reaction and product, has the advantage of safe and environment-friendly and suitable industrialization.
To achieve the above object, technical solution provided by the invention are as follows:
Firstly, preparing this intermediate of azido compound by serialization micro passage reaction, the azido compound can
Think it is well known in the art have general formula structure be RN3Compound, preferably can be nitrine sulfoacid compound.
First aspect present invention provides the method that serialization microchannel plate should prepare nitrine sulfoacid compound, by hydrazine sulphur
The aqueous solution of acyl compound and sodium nitrite is prepared in micro passage reaction.
Wherein, R is substituent group commonly used in the art, such as alkyl, alkoxy, aryl etc..It is more preferably methyl, methylbenzene
Base, to dodecylphenyl or p-methoxyphenyl.
The two step serialization microchannel plates that second aspect of the present invention can be realized nitrine sulfoacid compound are answered, by hydrazine chemical combination
After object reacts in first micro passage reaction with sulfonyl chloride compound, continue micro- at second with the aqueous solution of sodium nitrite
In channel reactor reaction can serialization be prepared,
Wherein, R is substituent group commonly used in the art, such as alkyl, alkoxy, aryl etc..It is more preferably methyl, methylbenzene
Base, to dodecylphenyl or p-methoxyphenyl.
The above-mentioned azido compound being prepared through two step serializations of the present invention can be further through third microchannel plate
Device preparation is answered to train southern intermediate.Specifically, third aspect present invention provides under the action of nitrine sulfoacid compound, formula III
The further serialization microchannel plate that compound prepares the southern intermediate formula IV compound of training in micro passage reaction is answered,
Wherein, R1It is preferably TBS or TBDMS for hydroxyl protection base.
The increase separation equipment of above-mentioned second microchannel and the third micro passage reaction property of can choose.
Specially feed pump 1 is sulfonyl chloride compound or the mixed liquor of its organic solvent;If methylsufonyl chloride is without being equipped with
At solution, and benzene sulfonyl chloride, paratoluensulfonyl chloride, to dodecyl benzene sulfonyl chloride or to Methoxybenzenesulfonyl chloride and organic solvent
Mixed liquor be feeding liquid etc.;
Feed pump 2 is hydrazine hydrate;
Feed pump 3 is sodium nitrite in aqueous solution;
Feed pump 4 is organic solvent;
Feed pump 5 is the mixed liquor of formula III compound and alkali;
Feed pump 6 is water.
Organic solvent described above can be the single molten of ethers, esters, arene, alkyl halide hydro carbons or alcohols solvent
Agent or mixed solvent.
The ether solvent is tetrahydrofuran or 2- methyltetrahydrofuran;The esters solvent is ethyl acetate, formic acid second
Ester or isopropyl acetate;The alcohols solvent is ethyl alcohol or isopropanol.
The aromatic hydrocarbon solvent is toluene;The halogenated alkanes solvents are methylene chloride.
The alkali is organic base, such as triethylamine, morpholine, N-methylmorpholine, DBU, potassium tert-butoxide, sodium tert-butoxide, diisopropyl
Base ethamine, pyridine, DMAP, triethylene diamine or tetramethylethylenediamine etc..
The temperature of the reaction is controlled at 0 DEG C~100 DEG C.
Above-mentioned multistep serialization microchannel plate should the property of can choose increase separation equipment.
Micro passage reaction used in the present invention can be single channel, multichannel, and the micro passage reaction can be
Multi-disc micro passage reaction is connected in series, and shape is U-shaped, T-type, Y type or cross type etc..
The microchannel plate that multistep continuous reaction of the present invention belongs to a wire type is answered, and has the advantage of safety and environmental protection.This hair
The microchannel plate that bright multistep continuous reaction belongs to a wire type is answered, and has the significant advantage in technical effect.Such as nitrine chemical combination
In the serialization preparation process of object, the prior art does not apply to the serialization of two steps, because of the substitution connection that the first step generates
Ammoniate is solid.However, the present invention continues to continue to react with the acid that first step microchannel plate should generate, will solve
The technical issues of certainly microchannel plate answers middle solid to make microchannel plate that should block, not can be carried out, so that second step microchannel plate should be able to
It is enough normally carried out, also, waste liquid is further reduced and more environmentally-friendly, energy conservation.
Figure of description
Fig. 1 is multistep serialization microchannel response diagram
Specific embodiment
For a further understanding of the present invention, exist below with reference to embodiment to serialization micro passage reaction provided by the invention
Application in pharmaceutical synthesis is described in detail.It is to be appreciated that the description of these embodiments is only further description
Feature of the invention, rather than the limitation to the scope of the invention or scope of the invention as claimed.
Embodiment 1:
Feed pump 1: methylsufonyl chloride
Feed pump 2: hydrazine hydrate
Feed pump 3: sodium nitrite in aqueous solution
Feed pump 4: methylene chloride
Feed pump 5: the mixed liquor of formula III compound and triethylamine
Feed pump 6: water
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, organic layer carries out subsequent reactions, and feed pump 5 starts the mixed liquor into formula III compound and alkali, mixed online
Reaction (2min~10min) is closed, temperature (20~80 DEG C) are arranged in reaction module, according to reaction dissolvent such as methylene chloride reaction module
Back pressure is needed to prevent temperature from increasing solvent evaporation, the reaction water inlet of node feed pump 6 carries out on-line cooling and is quenched, and it is molten to obtain product
Liquid.White solid, yield 90%, purity 98% are obtained through processing.
Embodiment 2:
Feed pump 1: the mixed liquor of paratoluensulfonyl chloride and toluene
Feed pump 2: hydrazine hydrate
Feed pump 3: sodium nitrite in aqueous solution
Feed pump 4: methylene chloride
Feed pump 5: the mixed liquor of formula III compound and triethylamine
Feed pump 6: water
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, organic layer carries out subsequent reactions, and feed pump 5 starts the mixed liquor into formula III compound and alkali, mixed online
Reaction (2min~10min) is closed, temperature (20~80 DEG C) are arranged in reaction module, according to reaction dissolvent such as methylene chloride reaction module
Back pressure is needed to prevent temperature from increasing solvent evaporation, the reaction water inlet of node feed pump 6 carries out on-line cooling and is quenched, product solution processing
Obtain white solid, yield 89%, purity 98.5%.
Embodiment 3:
Feed pump 1: the mixed liquor of benzene sulfonyl chloride and dimethylbenzene
Feed pump 2: hydrazine hydrate
Feed pump 3: sodium nitrite in aqueous solution
Feed pump 4: methylene chloride
Feed pump 5: the mixed liquor of formula III compound and triethylamine
Feed pump 6: water
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, organic layer carries out subsequent reactions, and feed pump 5 starts the mixed liquor into formula III compound and alkali, mixed online
Reaction (2min~10min) is closed, temperature (20~80 DEG C) are arranged in reaction module, according to reaction dissolvent such as methylene chloride reaction module
Back pressure is needed to prevent temperature from increasing solvent evaporation, the reaction water inlet of node feed pump 6 carries out on-line cooling and is quenched, product solution processing
Obtain white solid, yield 88%, purity 97%.
Embodiment 4: methylsulphur acyl azide preparation
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, methylsulphur acyl azide dichloromethane solution, yield 80%.(due to the unstability of nitrine reagent, so using serialization
Reactor, while production while uses, avoid due to nitrine largely existing for risk)
Embodiment 5: p-toluene sulfonyt azide preparation
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, methylsulphur acyl azide dichloromethane solution, yield 75%.(due to the unstability of nitrine reagent, so using serialization
Reactor, while production while uses, avoid due to nitrine largely existing for risk).
Claims (10)
1. a kind of method that serialization microchannel plate should prepare sulfonyl azide compound, which is characterized in that by hydrazine sulphonyl chemical combination
The aqueous solution of object and sodium nitrite is prepared in micro passage reaction,
Wherein, R is alkyl, alkoxy or aryl.
2. a kind of method that serialization microchannel plate should prepare sulfonyl azide compound, which is characterized in that by hydrazine compound with
After sulfonyl chloride compound reacts in first micro passage reaction, continue the aqueous solution with sodium nitrite second microchannel
In reactor reaction can serialization be prepared,
Wherein, R is alkyl, alkoxy or aryl.
3. preparation method according to claim 1 or 2, which is characterized in that the R is methyl, aminomethyl phenyl, to dodecane
Base phenyl or p-methoxyphenyl.
4. a kind of serialization microchannel plate should prepare the method for training southern intermediate, which is characterized in that prepared in claims 1 or 2
Under the action of obtained nitrine sulfoacid compound, the mixed liquor of formula III compound and alkali is answered through further serialization microchannel plate
Southern intermediate formula IV compound is trained in preparation,
Wherein, R1For hydroxyl protection base.
5. the preparation method according to claim 4, which is characterized in that R1For TBS or TBDMS.
6. a kind of serialization microchannel plate should prepare the method for training southern intermediate, which is characterized in that mesyl chloride is feeding liquid, water
Conjunction hydrazine is feeding liquid, and sodium nitrite in aqueous solution is feeding liquid, and the mixed liquor of formula III compound and alkali is feeding liquid, organic solvent
For feeding liquid, water is feeding liquid, should prepare the southern intermediate formula IV compound of training through multistep serialization microchannel plate,
7. the preparation method according to claim 4 or 6, which is characterized in that the alkali is organic base.
8. the preparation method according to claim 4 or 6, which is characterized in that the organic solvent is ethers, esters, fragrance
The single solvent or mixed solvent of hydro carbons, alkyl halide hydro carbons or alcohols solvent.
9. the preparation method according to claim 4 or 6, which is characterized in that the reaction temperature is 0 DEG C~100 DEG C.
10. the preparation method according to claim 4 or 6, which is characterized in that the multistep serialization microchannel plate Ying Zhongxuan
Selecting property increases separation equipment.
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CN110467161A (en) * | 2019-09-25 | 2019-11-19 | 山东省化工研究院 | A kind of synthesis technology of sodium azide |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN110467161A (en) * | 2019-09-25 | 2019-11-19 | 山东省化工研究院 | A kind of synthesis technology of sodium azide |
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