CN101768158B - Tiotropium bromide anhydride and preparation method thereof - Google Patents
Tiotropium bromide anhydride and preparation method thereof Download PDFInfo
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- CN101768158B CN101768158B CN 201010045804 CN201010045804A CN101768158B CN 101768158 B CN101768158 B CN 101768158B CN 201010045804 CN201010045804 CN 201010045804 CN 201010045804 A CN201010045804 A CN 201010045804A CN 101768158 B CN101768158 B CN 101768158B
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Abstract
The invention discloses a method for preparing tiotropium bromide anhydride, which comprises the steps of: under the anhydrous and anaerobic condition, preparing an intermediate I by taking a special kettle bottom valve and a multi-functional reaction kettle as a reactor, taking a special filter as refining equipment and taking hydrobromic scopolamine as an initial raw material through reduction hydrogenation reaction; preparing an intermediate II by performing addition reaction of Grignard reagent and dimethyl oxalate in tetrahydrofuran, wherein the Grignard reagent is prepared from bromothiophene by taking tetrahydrofuran as a medium through iodine catalysis; preparing an intermediate III by performing ester exchange condensation reaction of the intermediate I and the intermediate II under the action of sodium; preparing an intermediate IV from the intermediate III through methylation bromination reaction; and preparing the tiotropium bromide anhydride by performing the activated carbon decoloration and recrystallization on the intermediate IV by using aqueous solution and acetonitrile methanol isopropyl ether solution. Compared with those in the prior art, reaction products of the method have the advantages of good quality, high yield, controlled reaction process, safe production and good environmental protection effect.
Description
Technical field
The present invention relates to field of medicine and chemical technology, more particularly, relate to a kind of thiatro bromoaminium anhydrous compound and preparation method thereof.
Background technology
Tiotropium bromide (Tiotropium Bromide) is got permission listing November calendar year 2001 in Holland; be used for the treatment of chronic obstructive pulmonary disease (COPD); its basic patent is EP418716; it is proposed September 12 nineteen ninety by German BoehringerIngelheim company; its denomination of invention is " Thienylcarboxylicacid ester of aminoalcohols; their quaternary products; their preparationand use of the compounds ", and what this patent was claimed is tiotropium bromide monohydrate and the synthetic route take bromo thiophene as starting raw material thereof and the purposes for the treatment of COPD etc.
The preparation process of thiatro bromoaminium anhydrous compound patent of invention (patent No.: ZL2006100548666) disclose a kind of take scopolamine hydrobromide as starting raw material the preparation prepare scopine (intermediate compound I) through hydrolysis reaction; Bromo thiophene and magnesium generation grignard reaction generate Grignard reagent and prepare two (2-thienyl) methyl glycolate (intermediate II) with dimethyl oxalate through addition reaction again; Intermediate compound I and intermediate compound I I are through two (2-thienyl) the oxyacetic acid Rhizome of Japanese Scopolia esters (intermediate III) of transesterify condensation reaction preparation; Intermediate III prepares tiotropium bromide crude product (intermediate compound IV) through the bromination reaction that methylates; Intermediate compound IV prepares operational path and the preparation method of thiatro bromoaminium anhydrous compound again through crystallization and recrystallization process.The disclosed reaction that preparation prepares scopine (intermediate compound I) through hydrolysis reaction take scopolamine hydrobromide as starting raw material of this patent of invention be one by ester group to the hydroxyl hydrolytic process, if reaction conditions control is bad, easily make the tropine hydrolysis generate different Rhizome of Japanese Scopolia by product; The Grignard reagent that the disclosed bromo thiophene of this patent of invention is made in ether and dimethyl oxalate in ether through addition reaction, separating just if this reaction makes ketone ester under Grignard reaction conditions can be immediately and another molecule Grignard reagent addition, the alcohol ester quality that then generates is high, the reaction conditions such as temperature of reaction, solvent is the key factor that affects reaction mass, if reaction conditions control is bad, quality and the yield of intermediate II will be affected; The quality of intermediate compound I and intermediate II directly affects the quality of end product thiatro bromoaminium anhydrous compound.
Summary of the invention
The contriver is by the optimization research to the thiatro bromoaminium anhydrous compound synthesis technique, be surprisingly found out that the preparation process of thiatro bromoaminium anhydrous compound that a kind of reaction product quality is good, yield is high, reaction process is controlled, success overcome the deficiencies in the prior art.
The purpose of this invention is to provide the preparation process of thiatro bromoaminium anhydrous compound that a kind of reaction product quality is good, yield is high, reaction process is controlled.
Specifically, the invention provides under control anhydrous and oxygen-free condition, be reactor with special still bottom valve and multifunctional reaction still, be purification apparatus with special strainer, under the anhydrous and oxygen-free condition, logical ammonia makes the reaction solution alkalization in the anhydrous ethanol medium, carry out that ester reduces, hydrogenation prepares scopine (intermediate compound I) take scopolamine hydrobromide as starting raw material with sodium borohydride, hydrogenchloride; Bromo thiophene under the anhydrous and oxygen-free condition take tetrahydrofuran (THF) as medium with the Grignard reagent of catalysis of iodine preparation and dimethyl oxalate in tetrahydrofuran (THF) under the cold condition through addition reaction, with dehydrated alcohol recrystallization preparation pair (2-thienyl) methyl glycolate (intermediate II); With intermediate compound I and intermediate compound I I the transesterify condensation reaction occurs under the sodium effect, with the neutralization of acid extraction alkali, dichloromethane extraction, two (2-thienyl) the oxyacetic acid Rhizome of Japanese Scopolia esters (intermediate III) of activated carbon decolorizing preparation; Through the bromination reaction that methylates, adopt vacuum gradient intensification drying mode to prepare tiotropium bromide crude product (intermediate compound IV) with intermediate III; Intermediate compound IV aqueous solution activated carbon decolorizing recrystallization, acetonitrile methanol isopropyl ether solution activated carbon decolorizing recrystallization, the vacuum drying method of gradient increased temperature is refined into the end product thiatro bromoaminium anhydrous compound.
The English name of the thiatro bromoaminium anhydrous compound of the present invention's preparation is Tiotropium Bromide, and chemical name is 6 β, 7 beta epoxides-3 α-[2-hydroxyl-2, two (2-thienyl) acetoxyl groups of 2-]-8,8-dimethyl-1 α H, 5 α H-tropane base bromides, structural formula is
Molecular formula is C
19H
22BrNO
4S
2, molecular weight is 472.42.
Be used for the special still bottom valve of the present invention and comprise valve body 1, Link Port 2 at the bottom of valve and the still, valve pocket 3, plunger 4, thread spindle 5, locating slot 6, positioned centrally plate 7, setscrew nut 8, handwheel 9, back tightening nut 10 and 11, discharge port 12, sealing-ring 13 and connect soon clip 14, plunger 4 be installed in the valve pocket 3 and with thread spindle 5 in succession, locating slot 6 leaves on thread spindle 5, thread spindle 5 is by positioned centrally plate 10, setscrew nut 8, back tightening nut 10 and 11 is fixed in the valve pocket 3, handwheel 9 is installed in the bottom of valve body 1, are connected with back tightening nut by setscrew nut 8 and are connected with valve body 1 bottom and thread spindle 5, discharge port 12 is opened the side at valve body, its outlet is between the Link Port at the bottom of positioned centrally plate 7 and valve and the still, link to each other with valve pocket 3 and communicate, plunger 4 usefulness sealing-rings 13 and valve pocket 3 driving fits, make valve pocket 3 be convenient to dismounting and cleaning with connecing soon clip 14, also can be with pneumatic, the mode such as electronic or surge replaces handwheel 9 mobile plungers 4.
Be used for the special multifunctional reaction still of the present invention and comprise reactor 1, support 2 and electric heating magnetic stirring apparatus 3, reactor 1 is cylindric barrel-shaped, top and the bottom respectively are provided with top cover 7 and the bottom 21 of hemisphere face shape, top cover 7 is connected with bottom and is connected with kettle by 2 lifting eye bolts 9 that are installed in the kettle both sides respectively, discoid annular groove filter plate 8 is installed between top cover 7 and kettle, the diameter of annular groove filter plate 8 is less than or equal to the maximum diameter of top cover 7, sealing-ring 10 is installed between annular groove filter plate 8 and top cover 7 and the kettle, the kettle of reactor 1 is provided with heat preservation sandwich layer 11, heat preservation sandwich layer 11 communicates with closure head insulation interlayer 24 and bottom heat preservation sandwich layer 25, cooling fluid is advanced 13 and is installed in the kettle bottom near a side of the kettle of bottom 21, communicate with heat preservation sandwich layer 11 and to link to each other, cooling liquid outlet 12 is installed in kettle top near the opposite side of the kettle of top cover 7, communicate with heat preservation sandwich layer and to link to each other, charging opening 14 and distiller interface 15 are installed in kettle top near annular groove filter plate 8 places, communicate with kettle, thermometric 17, inflation inlet 18, thief hole 19 communicates with kettle and is installed in the kettle bottom near bottom 21 places, form 16 is installed on kettle bottom inflation inlet 18, magnetic stir bar 20 is placed in the kettle, support 2 comprises rotating shaft 22, base plate 26 and universal caster wheel 23, rotating shaft 22 is installed in the top of support 2, reactor 1 is installed on the support 2 by rotating shaft 22, and can carry out Arbitrary Rotation by rotating shaft 22, electric heating magnetic stirring apparatus 3 is installed on the base plate 26 of support 2, universal caster wheel 23 is installed under the base plate 26 of support 2, and support 2 can carry out any direction by universal caster wheel 23 and move.
Be used for the special strainer of the present invention and comprise filter top cover 1, annular groove filter plate 2 and 3, lauter tub 4 and filter bottom 5, feed-pipe 6, inert gas inleting pipe 7, rare gas element escape pipe 8, cooling liquid outlet 9, coolant return line 10, temperature measuring gauge 11 is installed in respectively on the filter top cover 1, filter top cover 1 is established thermal insulation layer 12 and interlayer 13, lauter tub 4 cylindrical tubbiness, be positioned at the bottom of filter top cover 1, be provided with thermal insulation layer 27, interlayer 28, outer metal plates 15, middle level metal sheet 16 and inner layer metal plate 17, filter bottom 5 is positioned at the bottom of lauter tub 4, be provided with discharge nozzle 18 and cooling liquid inlet 19, thermal insulation layer 20 and interlayer 21, it is planar that filter top cover 1 is hemisphere, be installed in the top of lauter tub 4 by bolt 22 and 23, annular groove filter plate 2 is in the form of annular discs to be installed between the top of filter top cover 1 and lauter tub 4, the bottom of lauter tub 4 by bolt 24 with are connected the filter bottom 5 planar with being down hemisphere and are connected, feed-pipe 6 runs through 1 sealing of filter top cover and is installed in filter top cover 1 central authorities, port at the feed-pipe 6 that runs through filter top cover 1 Internal Spherical Surface is installed feed liquid shower nozzle 14, feed-pipe 6 at filter top cover 1 spherical outside surface is installed rare gas element escape pipe 8, keep suitable distance between the endosphere end face of feed liquid shower nozzle 14 and annular groove filter plate 2 and filter top cover 1, cooling liquid outlet 9 and temperature measuring gauge 11 are installed in a side of filter top cover 1 centered by feed-pipe 6, inert gas inleting pipe 7 is installed in the opposite side of filter top cover 1, inert gas inleting pipe 7 runs through filter top cover 1, it runs through between the port of filter top cover 1 part and annular groove filter plate 2 and filter top cover 1 Internal Spherical Surface and keeps certain distance, coolant return line 10 is positioned at the opposite side of cooling liquid outlet 9, be installed between the top of filter top cover 1 and lauter tub 4, with filter closure head insulation layer 12, lauter tub thermal insulation layer 27, filter bottom thermal insulation layer 20 communicates, filter bottom 5 is installed in the bottom of lauter tub 4 by bolt 24 and 25, annular groove filter plate 3 is in the form of annular discs to be installed between the bottom of filter bottom 5 and lauter tub 4, discharge nozzle 18 runs through 5 sealings of filter bottom and is installed in filter bottom 5 central authorities, the port of discharge nozzle 18 that runs through filter bottom 5 is concordant with the Internal Spherical Surface of filter bottom 5, cooling fluid is entered 19 the same sides that are positioned at coolant return line 10, be installed on the filter bottom 5, link to each other with filter bottom thermal insulation layer 20 and to communicate, coolant return line 26 is positioned at cooling fluid and advances 19 opposite side, be installed between the bottom of filter bottom 5 and lauter tub 4, with filter closure head insulation layer 12, lauter tub thermal insulation layer 27, filter bottom thermal insulation layer 20 communicates, and coolant return line 10 and 26 is used respectively ready-packaged joint 29,30 and 31,32 loading and unloading; The hemisphere face inner and outer diameter of filter top cover 1 and bottom 5 and cover rim 33, the inner and outer diameter of 34 width and lauter tub 4 and bucket are identical or bigger along 35 width, feed-pipe 6 and discharge nozzle 18 are on same vertical centering control axis, the internal diameter of feed-pipe 6 greater than or etc. the internal diameter of discharge nozzle 18, cooling fluid is advanced 19 internal diameter more than or equal to the internal diameter of cooling liquid outlet 9, the internal diameter of inert gas inleting pipe 7 is more than or equal to the internal diameter of rare gas element escape pipe 8, annular groove filter plate 2 is identical with 3 diameter and all be slightly larger than the maximum inner diameter of filter top cover 1 and bottom 5 and the internal diameter of lauter tub 4, and coolant return line 10 is identical with 26 internal diameter.
The effect that the present invention is useful
1, the invention provides a kind of reaction product quality is good, yield is high, reaction process is controlled thiatro bromoaminium anhydrous compound and preparation method thereof.
2, compared with the prior art, preparation process of thiatro bromoaminium anhydrous compound reacting final product purity of the present invention reaches 99.9%, and yield improves 25%.
3, compared with the prior art, preparation process of thiatro bromoaminium anhydrous compound of the present invention can effectively be controlled anhydrous, anaerobic reaction conditions, prevents that side reaction from occuring, and improves reaction mass.
4, compared with the prior art, preparation process of thiatro bromoaminium anhydrous compound of the present invention can make and react completely, and effectively reduces the impurity of reaction.
5, compared with the prior art, preparation process of thiatro bromoaminium anhydrous compound of the present invention can effectively avoid hazardous compound to production operation personnel's harm, and safety in production and environmental protection benefit are good.
6, the structural identification test-results shows, the thiatro bromoaminium anhydrous compound structural formula of the present invention's preparation is
, molecular formula is C
19H
22BrNO
4S
2, molecular weight is 472.42.
(1) to record molecular formula consistent with this compound molecule formula with the determination of elemental analysis value for the high resolution mass spectrum of sample.
(2) in the structure
The feature performance of (fragment 1): IR composes signify hydroxy, the absorption peak of two keys.
1HNMR and
13The low territory, place of CNMR (DEPT) spectrum shows three groups of totally six protons and six carbon;
13The low field of CNMR spectrum also shows two peaks that quaternary carbon is overlapping; Two thiphene ring symmetries have been described.
1There is a reactive hydrogen the low field of HNMR spectrum;
13There is an adjacent oxygen quaternary carbon CNMR spectrum midfield.These information are all supported the existence of this fragment.
(3) in the structure
The feature performance of (fragment 2): show ester carbonyl group, ternary cyclic ethers, the absorption peak of methyl in the IR spectrum.
1HNMR and
13CNMR spectrum High-Field zone shows two n-formyl sarcolysine bases; High, midfield is regional to have shown the symmetrical or overlapping of methylene radical, methyne,
13The carbonyl peak that the CNMR spectrum is minimum.These information are all supported the existence of this fragment.
(4) linking to each other of fragment 1 and fragment 2 shown that carbonyl carbon in the fragment 2 is relevant with hydroxyl proton in the fragment 1 and added their confirmation by nucleus magnetic resonance distant relation spectrum.
(5) type of the proton number of NMR spectrum demonstration, carbonatoms, carbon all meets the requirement of this chemical structure.
(6) the base peak m/z392[M of ESI-MS spectrum demonstration]
+With the not brominated molecular formula C of this compound
19H
22NO
4S
2Molecular weight conform to, ultimate analysis records content and this compound molecule formula C of Br
19H
22BrNO
4S
2The theoretical amount of middle Br is basically identical.
(7) in sum, the chemical structure of sample can be proved conclusively and be thiatro bromoaminium anhydrous compound.
Description of drawings
Figure shown in Figure 1 is the thiatro bromoaminium anhydrous compound synthetic route, wherein 1 is scopine (intermediate compound I) synthetic route, the 2nd, two (2-thienyl) methyl glycolate (intermediate II) synthetic routes, the 3rd, two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester (intermediate III) synthetic routes, the 4th, tiotropium bromide crude product (intermediate compound IV) synthetic route.
Figure shown in Figure 2 is still bottom valve front section view, and wherein 1 is valve body, the 2nd, and the Link Port at the bottom of valve and the still, the 3rd, valve pocket, the 4th, plunger, the 5th, thread spindle, the 6th, locating slot, the 7th, positioned centrally plate, the 8th, setscrew nut, the 9th, handwheel, 10 and 11 is back tightening nuts, the 12nd, discharge port, the 13rd, sealing-ring, the 14th, connect soon clip.
Figure shown in Figure 3 is polyfunctional reactant kettle device elevation cross-sectional view, and wherein 1 is reactor, the 2nd, and support, the 3rd, electric heating magnetic stirring apparatus, the 4th, tensimeter, the 5th, discharge port, the 6th, valve, the 7th, top cover, the 8th, annular groove filter plate, the 9th, lifting eye bolt, the 10th, sealing-ring, the 11st, kettle heat preservation sandwich layer, the 12nd, cooling liquid outlet, the 13rd, cooling liquid inlet, the 14th, charging opening, the 15th, distiller interface, the 16th, form, the 17th, temperature-measuring port, the 18th, inflation inlet, the 19th, thief hole, the 20th, magnetic stir bar, the 21st, bottom, the 22nd, rotating shaft, the 23rd, universal caster wheel, the 24th, closure head insulation interlayer, the 25th, bottom heat preservation sandwich layer, the 26th, support base plate.
Figure shown in Figure 4 is the strainer elevation cross-sectional view, and wherein 1 is the filter top cover, and 2 and 3 is annular groove filter plates, the 4th, lauter tub, the 5th, filter bottom, the 6th, feed-pipe, the 7th, inert gas inleting pipe, the 8th, rare gas element escape pipe, the 9th, cooling liquid outlet, the 10th, filter top cover coolant return line, the 11st, temperature measuring gauge, the 12nd, filter closure head insulation layer, the 13rd, filter top cover interlayer, the 14th, feed liquid shower nozzle, the 15th, lauter tub outer metal plates, the 16th, lauter tub middle level metal sheet, the 17th, lauter tub inner layer metal plate, the 18th, discharge nozzle, the 19th, cooling liquid inlet, the 20th, filter bottom thermal insulation layer, the 21st, filter bottom interlayer, 22,23,24, the 25th, bolt, the 26th, filter bottom coolant return line, the 27th, the lauter tub thermal insulation layer, the 28th, lauter tub interlayer, 29,30,31, the 32nd, ready-packaged joint, the 33rd, filter top cover cover rim, the 34th, filter bottom cover rim, the 35th, lauter tub bucket edge.
Embodiment
1, the preparation of scopine (intermediate compound I)
Under control anhydrous and oxygen-free condition, be reactor with special still bottom valve and multifunctional reaction still, be purification apparatus with special strainer, get scopolamine hydrobromide 5.7g (0.013mol), add dehydrated alcohol 60～80ml, ammonia alkalizes to pH8～9.Gradation adds the about 5.1g of sodium borohydride (0.1353mol), 10～20 ℃ of stirring reactions, and thin layer is followed the tracks of reaction, about 10～12h of reaction times.The hydrogenchloride acidifying adds the dilution of 70～130ml anhydrous diethyl ether to pH1～2, filters.Filter cake adds 50～70ml methylene dichloride, and ammonia alkalizes to pH7～8.Suction filtration divides 3 washings with 30～50ml methylene dichloride.Merging filtrate, 25 ℃ of following evaporated under reduced pressure get the intermediate compound I white solid, yield about 83%.
2, the preparation of two (2-thienyl) methyl glycolate (intermediate compound I I)
Under control anhydrous and oxygen-free condition, be reactor with special still bottom valve and multifunctional reaction still, be purification apparatus with special strainer, getting 41.8g (0.2487mol) bromo thiophene is dissolved in 40～60ml anhydrous tetrahydro furan (sodium is dry), be added drop-wise in 90～110ml anhydrous tetrahydro furan (sodium is dry) solution of 6.78g magnesium chips (0.2790mol) and 2 iodine grains, drip and finish, stir 4～5h, backflow 0.5h cools off for subsequent use.
Get 13.34g (0.1130mol) dimethyl oxalate and be dissolved in 40～60ml anhydrous tetrahydro furan (sodium is dry), be cooled to 10 ± 5 ℃, be added dropwise to above-mentioned grignard solution, drip and finish, stirring reaction 4～5h, decompression steams tetrahydrofuran solvent to thick, drip 4～8% dilute sulphuric acids to pH1～2, use dichloromethane extraction, tell organic layer, anhydrous sodium sulfate drying filters evaporate to dryness, 20～40ml dehydrated alcohol recrystallization, drying gets intermediate compound I I, yield about 62%.
3, the preparation of two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester (intermediate compound I I I)
Under control anhydrous and oxygen-free condition, be reactor with special still bottom valve and multifunctional reaction still, be purification apparatus with special strainer, get intermediate compound I I 12.64g (0.0497mol) and intermediate compound I 7.0g (0.0451mol), add toluene 30～50ml, sodium 0.50～0.78g, be heated to 70～80 ℃ of stirring reactions, the while decompression vacuum pumping, balance drips toluene takes the methyl alcohol of reaction generation away, add toluene 80～100ml behind reaction 5～7h, cooling drips 5% hydrochloric acid solution to pH1～3, with toluene 50～70ml washing 3 times, add 8% yellow soda ash liquid to pH 9～10, methylene dichloride 60～80ml extraction 3 times, water 100～120ml washs 3 times to pH 7～7.5.Use anhydrous sodium sulfate drying, filter, divide 2 washings, evaporated under reduced pressure with methylene dichloride 50～70ml.The acetonitrile dissolving, activated carbon decolorizing filters recrystallization.Vacuum drying gets intermediate III, yield about 76%.
4, the preparation of tiotropium bromide crude product (intermediate compound IV)
Under control anhydrous and oxygen-free condition, be reactor with special still bottom valve and multifunctional reaction still, be purification apparatus with special strainer, get 10g (0.0265mol) intermediate III and be dissolved in 140～160ml acetonitrile-methylene dichloride (1: 1.1) solution, be chilled to≤3 ℃.Get again and be chilled to≤-10 ℃ the about 14.5g of monobromethane (0.1527mol), join in the reactor that fills front solution, seal fasteningly, room temperature reaction 30～48h filters, washing, adopt the gradient increased temperature boulton process, first at 40 ℃ of vacuum-drying 2h, be warming up to again 80 ℃ of vacuum-drying 〉=8h, namely get the thiophene holder and smell ammonium crude product (intermediate compound IV), yield about 96%.
5, the preparation of thiatro bromoaminium anhydrous compound
Be reactor with special still bottom valve and multifunctional reaction still, be purification apparatus with special strainer, get tiotropium bromide crude product (intermediate compound IV) 10g, add water 20～40ml, heating for dissolving, add 0.03gEDTA-2Na and gac 1～2g decolouring, filtration washing, filtrate cooling crystallization, filtration washing, the wet product of crystallization are with 150～250ml acetonitrile-methanol solution (9: 1) heating for dissolving, add gac 1～2g decolouring, filtration washing is chilled to room temperature, add 500～700ml isopropyl ether crystallization, filtration washing.The oven dry of gradient increased temperature boulton process gets the finished product thiatro bromoaminium anhydrous compound, yield about 88%.
Claims (1)
1. preparation process of thiatro bromoaminium anhydrous compound, it is characterized in that it is under control anhydrous and oxygen-free condition, be reactor with special still bottom valve and multifunctional reaction still, be purification apparatus with special strainer, logical ammonia makes the reaction solution alkalization in anhydrous ethanol medium take scopolamine hydrobromide as starting raw material, uses sodium borohydride, hydrogenchloride carries out the ester reduction, hydrogenation is with hydrogenchloride acidifying pH1～2, add the anhydrous diethyl ether dilution, filter, filter cake adds methylene dichloride, ammonia alkalization pH7～8, suction filtration, divide 3 washings, merging filtrate, 25 ℃ of following evaporated under reduced pressure with methylene dichloride, get scopine, i.e. intermediate compound I; Bromo thiophene take tetrahydrofuran (THF) as medium with the Grignard reagent of catalysis of iodine preparation and dimethyl oxalate in tetrahydrofuran (THF) under the cold condition through addition reaction, drip dilute sulphuric acid to pH1～2, use dichloromethane extraction, tell organic layer, anhydrous sodium sulfate drying, filter, evaporate to dryness, dehydrated alcohol recrystallization, drying, get two (2-thienyl) methyl glycolate, i.e. intermediate compound I I; The transesterify condensation reaction occurs under the sodium effect with intermediate compound I and intermediate compound I I, while decompression vacuum pumping, balance drip toluene makes the methyl alcohol of reaction generation take cooling away, drip dilute hydrochloric acid liquid to pH1～3, with toluene wash 3 times, add 8% yellow soda ash liquid to pH 9～10, dichloromethane extraction 3 times, water washing 3 times is to pH 7～7.5, use anhydrous sodium sulfate drying, filter, use washed with dichloromethane, evaporated under reduced pressure, the acetonitrile dissolving, activated carbon decolorizing filters, recrystallization, vacuum drying, two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester, i.e. intermediate III; Through the bromination reaction that methylates, adopt vacuum gradient intensification drying mode to prepare tiotropium bromide crude product, i.e. intermediate compound IV with intermediate III; Intermediate compound IV aqueous solution activated carbon decolorizing recrystallization, acetonitrile methanol isopropyl ether solution activated carbon decolorizing recrystallization, the vacuum drying method of gradient increased temperature is refining to be formed; The English name of described thiatro bromoaminium anhydrous compound is Tiotropium Bromide, and chemical name is 6 β, 7 beta epoxides-3 α-[2-hydroxyl-2, two (2-thienyl) acetoxyl groups of 2-]-8, and 8-dimethyl-1 α H, 5 α H-tropane base bromides, structural formula is
Molecular formula is C
19H
22BrNO
4S
2, molecular weight is 472.42; The structural formula of described intermediate compound I, intermediate II, intermediate III is respectively
Intermediate compound I intermediate II intermediate III
Described special still bottom valve comprises valve body 1, Link Port 2 at the bottom of valve and the still, valve pocket 3, plunger 4, thread spindle 5, locating slot 6, positioned centrally plate 7, setscrew nut 8, handwheel 9, back tightening nut 10 and back tightening nut 11, discharge port 12, sealing-ring 13 and connect soon clip 14, plunger 4 is installed in the valve pocket 3 and with thread spindle 5 and is connected, locating slot 6 leaves on thread spindle 5, thread spindle 5 is by positioned centrally plate 7, setscrew nut 8, back tightening nut 10 and back tightening nut 11 are fixed in the valve pocket 3, handwheel 9 is installed in the bottom of valve body 1, are connected with back tightening nut by setscrew nut 8 and are connected with valve body 1 bottom and thread spindle 5, discharge port 12 is opened the side at valve body 1, its outlet is between the Link Port 2 at the bottom of positioned centrally plate 7 and valve and the still, link to each other with valve pocket 3 and communicate, plunger 4 usefulness sealing-rings 13 and valve pocket 3 driving fits, its use connects clip 14 soon makes valve pocket 3 be convenient to dismounting and cleaning, and its handwheel 9 can be with pneumatic, electronic or hydraulically operated equipment replaces; Described special multifunctional reaction still comprises reactor 1, support 2 and electric heating magnetic stirring apparatus 3, reactor 1 is cylindric barrel-shaped, top and the bottom respectively are provided with top cover 7 and the bottom 21 of hemisphere face shape, top cover 7 is connected with bottom and is connected with kettle by 2 lifting eye bolts 9 that are installed in the kettle both sides respectively, discoid annular groove filter plate 8 is installed between top cover 7 and kettle, sealing-ring 10 is installed between annular groove filter plate 8 and top cover 7 and the kettle, the kettle of reactor 1 is respectively equipped with the heat preservation sandwich layer 11 that communicates with closure head insulation interlayer 24 and bottom heat preservation sandwich layer 25, cooling liquid inlet 13 is installed in the kettle bottom near a side of the kettle of bottom 21, link to each other with heat preservation sandwich layer 11 and to communicate, cooling liquid outlet 12 is installed in kettle top near the opposite side of the kettle of top cover 7, link to each other with heat preservation sandwich layer 11 and to communicate, charging opening 14 and distiller interface 15 are installed in kettle top near annular groove filter plate 8 places, communicate with kettle, temperature-measuring port 17, inflation inlet 18 and thief hole 19 communicate with kettle, be installed in the kettle bottom near bottom 21 places, form 16 is installed on kettle bottom inflation inlet 18, magnetic stir bar 20 is placed in the kettle, support 2 comprises rotating shaft 22, base plate 26 and universal caster wheel 23, rotating shaft 22 is installed in the top of support 2, reactor 1 is installed on the support 2 by rotating shaft 22, electric heating magnetic stirring apparatus 3 is installed on the base plate 26 of support 2, universal caster wheel 23 is installed under the base plate 26 of support 2, reactor 1 can carry out Arbitrary Rotation by rotating shaft 22, and the diameter of annular groove filter plate 8 is less than or equal to the maximum diameter of top cover 7; Described special strainer comprises filter top cover 1, annular groove filter plate 2 and annular groove filter plate 3, lauter tub 4 and filter bottom 5, feed-pipe 6, inert gas inleting pipe 7, rare gas element escape pipe 8, cooling liquid outlet 9, coolant return line 10, temperature measuring gauge 11 is installed in respectively on the filter top cover 1, filter top cover 1 is established thermal insulation layer 12 and interlayer 13, lauter tub 4 is positioned at the bottom of filter top cover 1, be provided with thermal insulation layer 27, interlayer 28, outer metal plates 15, middle level metal sheet 16 and inner layer metal plate 17, filter bottom 5 is in the bottom of lauter tub 4, be provided with discharge nozzle 18, cooling liquid inlet 19, thermal insulation layer 20 and interlayer 21, it is planar that filter top cover 1 is hemisphere, be installed in the top of lauter tub 4 by bolt 22 and bolt 23, annular groove filter plate 2 is in the form of annular discs to be installed between the top of filter top cover 1 and lauter tub 4, lauter tub 4 is the cylinder tubbiness, are connected with bolt and are connected with filter bottom 5 by bolt 24 in its underpart, it is planar that filter bottom 5 is down hemisphere, feed-pipe 6 runs through the central authorities that 1 sealing of filter top cover is installed in filter top cover 1, port at the feed-pipe 6 that runs through filter top cover 1 Internal Spherical Surface is installed feed liquid shower nozzle 14, keep suitable distance between the endosphere end face of feed liquid shower nozzle 14 and annular groove filter plate 2 and filter top cover 1, cooling liquid outlet 9 and temperature measuring gauge 11 are installed in a side of filter top cover 1 centered by feed-pipe 6, inert gas inleting pipe 7 is installed in the opposite side of filter top cover 1, inert gas inleting pipe 7 runs through between the Internal Spherical Surface of the port of filter top cover 1 Internal Spherical Surface and annular groove filter plate 2 and filter top cover 1 and keeps suitable distance, coolant return line 10 is positioned at the opposite side of cooling liquid outlet 9, be installed between the top of filter top cover 1 and lauter tub 4, with filter closure head insulation layer 12, lauter tub thermal insulation layer 27, filter bottom thermal insulation layer 20 communicates, filter bottom 5 is installed in the bottom of lauter tub 4 by bolt 24 and bolt 25, annular groove filter plate 3 is in the form of annular discs to be installed between the bottom of filter bottom 5 and lauter tub 4, discharge nozzle 18 runs through the central authorities that 5 sealings of filter bottom are installed in filter bottom 5, discharge nozzle 18 ports that run through filter bottom 5 Internal Spherical Surface are concordant with the Internal Spherical Surface of filter bottom 5, cooling liquid inlet 19 is positioned at the same side of coolant return line 10, be installed on the filter bottom 5, link to each other with filter bottom thermal insulation layer 20 and to communicate, coolant return line 26 is positioned at the opposite side of cooling liquid inlet 19, be installed between the bottom of filter bottom 5 and lauter tub 4, with filter bottom thermal insulation layer 20, lauter tub thermal insulation layer 27, filter closure head insulation layer 12 communicates, coolant return line 10 and coolant return line 26 are used respectively ready-packaged joint 29, ready-packaged joint 30 and ready-packaged joint 31, ready-packaged joint 32 loading and unloading, the hemisphere face inner and outer diameter of filter top cover 1 and bottom 5 and cover rim 33, the inner and outer diameter of the width of cover rim 34 and lauter tub 4 and bucket are identical or bigger along 35 width, feed-pipe 6 and discharge nozzle 18 are on same vertical centering control axis, the internal diameter of feed-pipe 6 is more than or equal to the internal diameter of discharge nozzle 18, the diameter of annular groove filter plate 2 and annular groove filter plate 3 is identical and be slightly larger than the maximum inner diameter of filter top cover 1 and filter top cover 5 and the internal diameter of lauter tub 4, the internal diameter of inert gas inleting pipe 7 is more than or equal to the internal diameter of rare gas element escape pipe 8, and coolant return line 10 is identical with the internal diameter of coolant return line 26.
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| CA2997501C (en) | 2015-09-04 | 2022-05-10 | Janssen Pharmaceutica Nv | Therapeutic compound for pain and synthesis thereof |
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