CN101230063B - Method for preparing tiotropium bromide - Google Patents
Method for preparing tiotropium bromide Download PDFInfo
- Publication number
- CN101230063B CN101230063B CN2008100810198A CN200810081019A CN101230063B CN 101230063 B CN101230063 B CN 101230063B CN 2008100810198 A CN2008100810198 A CN 2008100810198A CN 200810081019 A CN200810081019 A CN 200810081019A CN 101230063 B CN101230063 B CN 101230063B
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- CN
- China
- Prior art keywords
- reaction
- tiotropium bromide
- preparing
- anhydrous
- product
- Prior art date
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- 229960000257 tiotropium bromide Drugs 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 33
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 title claims abstract description 31
- 239000000047 product Substances 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- -1 tiotropium bromide anhydride Chemical class 0.000 claims abstract description 15
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000001953 recrystallisation Methods 0.000 claims abstract description 13
- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical compound C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 9
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 claims abstract description 7
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 claims abstract description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- 239000011777 magnesium Substances 0.000 claims abstract description 6
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 6
- 229960004499 scopolamine hydrobromide Drugs 0.000 claims abstract description 6
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 37
- 239000000543 intermediate Substances 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
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- WYZSHSYANZLLRM-UHFFFAOYSA-N 2-thiophen-2-yloxyacetic acid Chemical compound OC(=O)COC1=CC=CS1 WYZSHSYANZLLRM-UHFFFAOYSA-N 0.000 claims description 5
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 claims description 2
- 150000001649 bromium compounds Chemical class 0.000 claims description 2
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- 238000002604 ultrasonography Methods 0.000 claims description 2
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- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 7
- 238000003929 heteronuclear multiple quantum coherence Methods 0.000 description 7
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 6
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- 238000010521 absorption reaction Methods 0.000 description 6
- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 5
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- MQLXPRBEAHBZTK-SEINRUQRSA-M tiotropium bromide hydrate Chemical compound O.[Br-].C[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 MQLXPRBEAHBZTK-SEINRUQRSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000000207 volumetry Methods 0.000 description 1
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Abstract
The invention relates to the application of microwave and ultrasonic technologies in synthesizing tiotropium bromide anhydride, in particular to a method for preparing the refined product of a finished product, namely, tiotropium bromide anhydride through crystallization and recrystallization processes by using a crude product of tiotropium bromide prepared through bromization reaction after hydrolytic reaction of scopolamine hydrobromide under microwave function, substitution and coupling reaction of bromothiophene, magnesium, and oxalic acid dimethyl ester under the microwave function, and condensation reaction of scopine and thiophen methyl glycollate under the microwave function. Using the invention to prepare tiotropium bromide anhydride, not only the reaction time is short, the side reaction is less, and the yield rate is high in the room temperature condition, but also the product quality is stable, controllable, safe and effective.
Description
Technical field
The present invention relates to the application in synthetic thiatro bromoaminium anhydrous compound of microwave and ultrasonic technology, be specifically related to hydrolysis reaction, bromo thiophene and the magnesium of scopolamine hydrobromide under microwave action and dimethyl oxalate in the condensation reaction under microwave action of the replacement linked reaction under the ultrasonic wave effect, scopine and the sour methyl esters of thiophene ethanol after the tiotropium bromide crude product that bromination reaction prepares prepares the method for end product thiatro bromoaminium anhydrous compound highly finished product again through crystallization and recrystallization process.
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 this patent is claimed is tiotropium bromide monohydrate and is the synthetic route of starting raw material and the purposes of treatment COPD etc. with the bromo thiophene.By retrieval, the method for preparing at present tiotropium bromide is traditional synthesis technology, all there are long reaction time, by product is many, yield is low problem, for example, Liu Xianhua etc. report in " new synthetic process of tiotropium bromide " document: " with natural Scopolamine is that raw material synthesizes; use the ammoniacal liquor hydrolysis, then use duration and side reaction many, mainly obtain oscine; Hydrated barta hydrolysis Scopolamine 140 minutes are used in the laboratory, can obtain the scopine of 42% yield, but produce when amplifying and to prolong the reaction times, and long more scopine of following time of alkaline environment is converted into the ratio of oscine with regard to high more [first academic nd Annual Meeting collection of Shandong Province pharmaceutical society (descending), 2005 years] ".U.S. Patent Publication a kind of preparation method of tiotropium bromide (patent No. is: US005610163A), wherein disclose the scopine of following technical characterictic: 0.2mol and two (2-thiophene) ethyl glycolate of 0.2mol is dissolved in the toluene on specification sheets 7-11 hurdle, and adding 1.65g sodium, 90 ℃ of reactions, methyl alcohol with gained distillates under 500 millibars simultaneously, continue reaction after 5 hours, stir in the mixture with reaction mixture adding ice and hydrochloric acid, dried over sodium sulfate, filter, distillation, the acetonitrile recrystallization gets two (2-thiophene) oxyacetic acid Rhizome of Japanese Scopolia ester (embodiment 1); Specification sheets the 7th hurdle the 60th～61 row points out that wherein said two (2-thiophene) ethyl glycolate is made by dimethyl oxalate and 2-thiophene magnesium bromide; Disclose among the specification sheets embodiment 4 two (2-thiophene) oxyacetic acid Rhizome of Japanese Scopolia ester has been dissolved in the mixture of anhydrous methyl chloride and acetonitrile, add monobromethane (it is in 50% solution of acetonitrile), room temperature reaction 24 hours, filter, the methyl chloride washing and the following 35 ℃ of dryings that reduce pressure, obtain white crystals in the methanol/acetone, decompression is dry down.Therefore, guarantee tiotropium bromide stable and controllable for quality, safely and effectively under the prerequisite, shortening the reaction times, reducing side reaction product, improve yield is main purpose of the present invention.
Summary of the invention
The invention provides the application in synthetic thiatro bromoaminium anhydrous compound of a kind of microwave and ultrasonic technology, be specifically related to hydrolysis reaction, bromo thiophene and the magnesium of scopolamine hydrobromide under microwave action and dimethyl oxalate in the condensation reaction under microwave action of the replacement linked reaction under the ultrasonic wave effect, scopine and the sour methyl esters of thiophene ethanol after the tiotropium bromide crude product that bromination reaction prepares prepares the method for end product thiatro bromoaminium anhydrous compound highly finished product again through crystallization and recrystallization process.The structural formula of the thiatro bromoaminium anhydrous compound of the present invention's preparation is
, molecular formula is C
19H
22BrNO
4S
2, molecular weight is 472.42.Its synthetic route sees that Fig. 1, technical process see Fig. 2.
Embodiment
The preparation of scopine (intermediate one)
Get scopolamine hydrobromide, methyl alcohol, salt of wormwood, putting airtight wavelength is in the microwave normal pressure reactor of 0.1～100cm, under the room temperature condition after the rapid reaction, and evaporated under reduced pressure, add methylene chloride, filter, filter cake is given a baby a bath on the third day after its birth inferior with methylene dichloride, merging filtrate, anhydrous sodium sulfate drying, evaporated under reduced pressure makes scopine oily matter (intermediate one), and yield is 99.3%.
The preparation of two (2-thienyl) methyl glycolate (intermediate two)
Get bromo thiophene, magnesium chips, dimethyl oxalate, ether, put in the ultrasound reactor that frequency is 20～300KHZ, after the rapid reaction, in reaction solution, drip dilute sulphuric acid under the room temperature condition, tell the ether layer, wash washing, anhydrous sodium sulfate drying with aqueous sodium carbonate, evaporate to dryness, use the toluene recrystallization, make two (2-thienyl) methyl glycolate crystallisates (intermediate two), yield is 96.7%.
The preparation of two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester (intermediate three)
The intermediate two and intermediate one mixing of mole molecular ratio such as get, adding the rearmounted airtight wavelength of sodium is in 0.1～100cm microwave normal pressure reactor, under the room temperature condition after the rapid reaction, in reaction solution, add toluene, continue reaction, add the ethyl acetate dilution, water washing organic layer 2 times, anhydrous sodium sulfate drying, filter, evaporate to dryness is used the acetonitrile recrystallization, make two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester crystallisates (intermediate three), yield is 98.3%.
The preparation of tiotropium bromide product crude product
Get the solution that intermediate three is dissolved in anhydrous methylene chloride and anhydrous acetonitrile, cooling is got cold acetonitrile and is joined in the monobromethane that is chilled to same temperature, join in the solution that fills anhydrous methylene chloride and anhydrous acetonitrile, airtight, rise to room temperature reaction, filter, make the tiotropium bromide crude product.
Embodiment 5
Making with extra care of tiotropium bromide
Get the tiotropium bromide crude product, with acetonitrile-methanol solution, gac recrystallization twice, add ether in the recrystallization liquid and separate out crystallization, filter, vacuum-drying makes end product thiatro bromoaminium anhydrous compound highly finished product.
Industrial applicibility
Adopt the thiatro bromoaminium anhydrous compound of the inventive method preparation, carry out following experimental study, the result shows and the present invention prepares thiatro bromoaminium anhydrous compound not only the reaction time is short at ambient temperature, side reaction is few, yield is high, and constant product quality is controlled, safe and effective.
One, conclusive evidence chemical structure
1. ultimate analysis
1. instrument model: CARLO-ERBA 1106 elemental analysers
2. test result: see Table 1.
Table 1. ultimate analysis data list
| Analysis project | Measured value (%) | Theoretical value (%) |
| C | 48.41，48.52 | 48.30 |
| H | 4.76，4.72 | 4.69 |
| N | 3.03，3.07 | 2.96 |
| S | 13.61，13.59 | 13.55 |
| Br | 17.04，17.12 | 16.91 |
The determination of elemental analysis value of sample and theoretical value basically identical.The assay of sulphur and bromine is recorded by the semimicro volumetry.
2. UV spectrum
1. instrument model: HP-8452A ultraviolet-visible pectrophotometer
2. test condition: C
2H
5OH 0.1mol/L HCl 0.1mol/L NaOH
Sample concentration (μ g/ml) 21.45 21.49 21.46
3. test result: see Table 2.
The tabulation of table 2. ultraviolet spectrum data
| Solvent | λ(nm) | ε(×10 4) | E | λ(nm) | ε(×10 4) | E | Ownership |
| C 2H 5OH | 202 | 0.78 | 168.23 | 240 | 1.34 | 287.01 | Two keys |
| 0.1mol/L HCl | 202 | 1.23 | 261.14 | 238 | 1.30 | 279.96 | Two keys |
| 0.1mol/L NaOH | 218 | 1.21 | 259.66 | 238 | 1.41 | 305.03 | Two keys |
4. resolve: the main absorption ownership of sample UV spectrum is two keys.
3. infrared spectra
1. instrument model: Nicolet FTIR-670 infrared spectrometer
2. instrumental correction: polystyrene film
3. test condition: KBr pressed disc method
4. test result: see Table 3.
The tabulation of table 3. ir data
5. resolve
A, 3476,1078cm
-1Stretching vibration and carbon-oxygen singly-bound stretching vibration for hydroxyl.
B, 3093,3116,738cm
-1Be the hydrocarbon stretching vibration of thiphene ring, triatomic ring and the hydrocarbon rocking vibration of thiphene ring.
C, 2907,1436cm
-1Stretching vibration and flexural vibration for saturated hydrocarbon (methyl, methylene radical etc.).
D, 17121,1231cm
-1Be ester carbonyl stretching vibration and the stretching vibration of carbon oxygen singly-bound.
E, 1279,936,872cm
-1Stretching vibration of carbon oxygen and skeletal vibration for the ternary epoxy.
There are hydroxyl, thiophene, ternary epoxy, methyl, methylene radical and ester etc. in f, the ir data description architecture.
4. nuclear magnetic resonance spectrum
1. instrument model: Varian INOVA-400 nuclear magnetic resonance analyser
2. test condition: solvent DMSO-d6
1H,
13C, DEPT, COSY, HMQC, HMBC spectrum
3. test result:
Table 4. nucleus magnetic resonance
1H, COSY compose data list
| Sequence number | δ H | Proton number | Multiplicity (J/Hz) | COSY (position) |
| 4 4’ | 1.92，2.63，2.74 | 4 | d t 17.1，5.7 | 4’ 4 |
| N(CH 3) 2 | 3.09，3.21 | 6 | |
|
| 2 2’ | 3.48 | 2 | |
3 3’ |
| Sequence number | δ H | Proton number | Multiplicity (J/Hz) | COSY (position) |
| 3 3’ | 4.19，4.20 | 2 | 4 4’ | |
| 5 | 5.15 | 1 | t 5.7 | 4 4’ |
| 10 10’ | 6.89 | 2 | dd 3.5，4.9 | 9 9’11 11’ |
| 9 9’ | 7.11 | 2 | dd 1.1，3.5 | 10 10’ |
| OH | 7.35 | 1 | s | |
| 11 11’ | 7.52 | 2 | dd 1.2，4.7 | 10 10’ |
4. resolve
Two methyl are arranged in a, the structure.Two methyl are the n-formyl sarcolysine base, and are unimodal; The nitrogen and the unsymmetrical carbon of quaternary ammonium salt have similarity, so two methyl non-equivalences have two chemical displacement values.
Two methylene radical are arranged in b, the structure.The proton of 4,4 ' two methylene radical shows as non-equivalence, and the coupling of existing ortho position has again with the carbon coupling, has different chemical displacement values.
Five methynes are arranged in c, the structure.2,2 ' two methyne is overlapping, does not show coupling on collection of illustrative plates, be one unimodal; Though it is adjacent with oxygen, the influence of the tension force of triatomic ring is very big, and its chemical displacement value is in δ about 3.48.3,3 ' proton chemical shifts value is δ 4.19,4.20.It is not obvious that branch is split in the coupling of above-mentioned four protons, may weaken because of residing chemical environment makes its coupling ability, and the reference point that the COSY spectrum shows is also very weak.5 adjacent oxygen of proton, low of chemical shift, triplet.
Six on two key protons are arranged in d, the structure.Six protons on two thiphene ring are corresponding, overlapping one by one; The coupling of existing ortho position has long-range coupling again.10,10 ' proton respectively with two adjacent proton couplings, the dd peak is the ortho position coupling, coupling constant is big slightly.The dd peak of 9,9 ' proton is that an ortho position coupling and a digit pair are closed.The peak shape of 11,11 ' proton is also closed for an ortho position coupling and a digit pair, because of adjacent sulphur, and minimum of chemical shift.A hydroxyl proton is arranged in the structure, unimodal, disappear after adding heavy water.
The proton nmr spectra of e, sample has provided the information of n-formyl sarcolysine base, two symmetric thiphene ring, hydroxyl, methylene radical and methynes.
Table 5. nucleus magnetic resonance
13C, DEPT, HMQC, HMBC compose data list
| Sequence number | δ C | Carbonatoms | DEPT | HMQC (δ H) (δ C) | HMBC (position) |
| 4 4’ | 28.44 | 2 | ↓ | 1.86，2.61，2.69-28.63 | |
| N(CH 3) 2 | 47.31，55.82 | 2 | ↑ | 3.06-47.11，3.21-56.02 | |
| 2 2’ | 53.36 | 2 | ↑ | 3.48-53.16 |
| Sequence number | δ C | Carbonatoms | DEPT | HMQC (δ H) (δ C) | HMBC (position) |
| 5 | 63.54 | 1 | ↑ | 5.03-63.11 | |
| 3 3’ | 64.11 | 2 | ↑ | 4.16，4.23-65.12 | |
| 7 | 76.83 | 1 | OH | ||
| 9 9’ | 125.62 | 2 | ↑ | 7.06-125.13 | |
| 11 11’ | 126.37 | 2 | ↑ | 7.46-126.83 | |
| 10 10’ | 126.13 | 2 | ↑ | 6.84-126.11 | |
| 8 8’ | 146.29 | 2 | OH 9 9’ | ||
| 6 | 169.17 | 1 | OH 5 |
5. resolve
Two n-formyl sarcolysine bases are arranged in a, the structure, DEPT spectrum shows ↑.They have the reason of two chemical displacement values and hydrogen spectrum similar, and the HMQC spectrum is shown relevant with their proton.
Two methylene radical are arranged in b, the structure, DEPT spectrum shows ↓.Two carbon of 4,4 ' are overlapping, and the HMQC spectrum is shown relevant with their proton.
Five methynes are arranged in c, the structure.2,2 ', 3, four methynes of 3 ' are overlapping in twos.5 precedence methyl ownership is δ 63.54.
Six in two key CH carbon are arranged in d, the structure.Two thiphene ring symmetries, its six CH carbon are overlapping in twos, and the HMQC spectrum is shown relevant with their proton.
Three quaternary carbons are arranged in e, the structure.The carbon of minimum δ 169.17 of full spectrum, relevant with the OH proton by the demonstration of HMBC spectrum with 5, so ownership is 6 ester carbonyl group carbon.The carbon of inferior low δ 146.29, ownership is 8,8 ' thiphene ring quaternary carbon, adjacent sulphur and by HMBC compose show relevant with 9,9 ' proton with the OH proton.The saturated quaternary carbon of δ 76.83, relevant with the OH proton by the demonstration of HMBC spectrum, ownership is 7 carbon.
The carbonatoms of f, sample carbon spectrum conforms to this chemical structure with type, proved the existence of carbonyl, two thiphene ring, n-formyl sarcolysine base, methylene radical, methyne etc., and relevant spectrum all has reasonable corresponding points.
5. mass spectrum
1. instrument model: Q-Tof micro mass spectrograph
2. test condition: ESI source
3. resolve: this Compound C
19H
22BrNO
4S
2=472, its M=392 of deduction bromine.Obtain ion cluster m/z392[M by the ESI method]+; M/z393[M+1]
+M/z394[M+2]
+, meet the ESI rule, conform to this compound molecular weight.
6. heat is analyzed
1. instrument model: P-E DSC-7 differential scanning calorimeter P-E TG-7 thermogravimetric instrument
2. test condition:
3. resolve: the Onset value that the DSC spectrum obtains melting peak is 218.86 ℃.
7. powder x-ray diffraction analysis
1. instrument model: Bruker D8 Advance x-ray diffractometer
2. test condition: Target:Cu 40kv 40mA scanspeed 0.2
3. test result: see Table 6.
The tabulation of table 6.X-diffraction data
| d-value | 2Theta | I/Io |
| 5.83 | 15.31 | 75 |
| 5.62 | 15.69 | 50 |
| 4.84 | 18.13 | 100 |
| 4.73 | 18.62 | 48 |
| 4.06 | 22.11 | 75 |
| 4.11 | 21.67 | 85.0 |
8. integration analysis
1. determination of elemental analysis value and this compound theoretical value basically identical.
2. in the structure
Feature performance: IR composes signify hydroxy, the absorption peak of two keys.
1HNMR and
13The low territory, place of CNMR (DEPT) spectrum shows symmetric three groups of totally six protons and six carbon;
13Low of CNMR spectrum shows two quaternary carbon eclipsed peaks; 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 this segmental existence.
3. in the structure
Feature performance: 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 groups of n-formyl sarcolysine bases, and chemical displacement value differs certain distance, due to the asymmetry of quaternary ammonium salt nitrogen, the existence of quaternary ammonium salt is described promptly.
1HNMR and
13CNMR (DEPT) spectrum height, the methylene radical of the regional demonstration in midfield, methyne, symmetrical or overlapping.
13The carbonyl peak that the CNMR spectrum is minimum.These information are all supported this segmental existence.
4. the type of sample NMR spectrum proton number, carbonatoms, carbon all meets the requirement of this chemical structure.
5. sample ESI mass spectrum, the ion cluster that obtains [M]
+Conform to the chemical structure of this compound.
6. in sum, the chemical structure of sample can be proved conclusively and be tiotropium bromide.
Two, quality control standard
This product 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.Press dry product and calculate, contain C
19H
22BrNO
4S
2Must not be less than 98.0%.
[proterties] this product is white or off-white color crystalline powder; Odorless or odorless almost.
This product is dissolved in water, dissolves in methyl alcohol, and is molten in the ethanol part omitted, insoluble in chloroform or ether.
Fusing point is according to melting point determination (according to two appendix VI of Chinese Pharmacopoeia version in 2005 C), and the fusing point of this product is 216～219 ℃, decomposes during fusion.
[discriminating]
(1) gets this product, add water and make the solution that contains 15 μ g among every 1ml, measure, maximum absorption is arranged at the wavelength place of 238nm according to spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A).
(2) the infrared Absorption collection of illustrative plates of this product should be consistent with the reference substance collection of illustrative plates.
(3) this product shows the identification (two appendix III of Chinese Pharmacopoeia version in 2005) of tropane alkaloid class.
(4) aqueous solution of this product shows the identification (two appendix III of Chinese Pharmacopoeia version in 2005) of bromide.
[inspection]
It is an amount of that related substance is got this product, and the moving phase that adds under the assay item is made the solution that contains 0.004mg and 0.4mg among every 1ml respectively, and difference is solution and need testing solution in contrast.According to the method test under the assay, get contrast solution 20 μ l and inject liquid chromatograph, regulate the instrument detection sensitivity, make principal constituent chromatogram peak height be about the 10%-20% of registering instrument full range; Get each 20 μ l of need testing solution and contrast solution again, inject liquid chromatograph respectively, the record color atlas is to 4 times of principal constituent peak retention time, and as showing impurity peaks, each impurity peak area summation must not be greater than contrast solution main peak area (1.0%) in the color atlas of need testing solution.
Vitriol is got this product 0.1g, checks (two appendix VIII of Chinese Pharmacopoeia version in 2005 B) in accordance with the law, and the contrast liquor ratio made from standard potassium sulfate solution 0.5ml must not denseer (0.05%).
Weight loss on drying is got this product, is dried to constant weight at 105 ℃, subtracts weight loss and must not cross 1.0% (two appendix VIII of Chinese Pharmacopoeia version in 2005 L).
Residue on ignition must not be crossed 0.1% (two appendix VIII of Chinese Pharmacopoeia version in 2005 N).
Heavy metal is got the residue of leaving under the residue on ignition item, checks to contain (two appendix VIII of Chinese Pharmacopoeia version in 2005 H, second method) heavy metal and must not cross 10/1000000ths in accordance with the law.
It is an amount of that organic solvent residual is got this product, and accurate the title decides, and adds water and make dissolving and make the solution that contains 100mg among every 1ml, checks (Chinese Pharmacopoeia version appendix in 2005 VIII P) in accordance with the law, and methyl alcohol, acetonitrile, methylene dichloride and toluene all must not cross 0.03%.
[assay] measured according to high performance liquid chromatography (Chinese Pharmacopoeia version appendix in 2005 V D).
Chromatographic condition and system suitability test are weighting agent with octadecylsilane chemically bonded silica; (phosphoric acid 5.5 adds water to 1000ml, and it is 3.2 that triethylamine is regulated pH)-acetonitrile (80: 20) is a moving phase with phosphoric acid solution; The detection wavelength is 238nm.Number of theoretical plate calculates by the tiotropium bromide peak should be not less than 2000, and the resolution of tiotropium bromide peak and adjacent peak should meet the requirements.
Assay method is got the about 20mg of this product, and accurate the title decides, and puts in the 50ml measuring bottle, adds to flow mutual-assistance dissolving and be diluted to scale, shakes up, and precision is measured 5ml, puts in the 50ml measuring bottle, adds moving phase and is diluted to scale, shakes up, and gets 20 μ l and injects liquid chromatograph, the record color atlas; The about 20mg of tiotropium bromide reference substance that other learns from else's experience 105 ℃ and is dried to constant weight measures with method.Press external standard method with calculated by peak area, promptly.
Detected result shows that the every index of thiatro bromoaminium anhydrous compound of the inventive method preparation all meets the regulation of above-mentioned quality control standard.
Three, stability study
This product is through influence factor (high light, high temperature, high humidity) test 10 days, accelerated test 6 months, test of long duration 24 months, and the result shows that every investigation index is not seen obvious change, steady quality.
Four, acute toxicity test
This product mouse stomach administration LD
50Be 1361.27mg/kg, mouse mainline administration LD50 is 41.56mg/kg.
Five, pharmacokinetic
Absorb rapidly in the capsule type inhalation aerosol powder body made from the thiatro bromoaminium anhydrous compound of the present invention preparation, suck and promptly reach the Plasma Concentration peak value after 5 minutes, be returned to Css after 60 minutes.Transformation period is about 5.8 days.Absolute bioavailability is 35%.Food does not influence its absorption.Plasma protein binding ratio is 75%.10% with the discharge from urine of medicine original shape.SM does not see that the drug accumulation phenomenon takes place.
Six, clinical study
In 163 examples to severe COPD patient through 12 all clinical trials, the result shows, suck above-mentioned powder inhalation (containing thiatro bromoaminium anhydrous compound 18 micrograms) every day for 1 time than the valley that sucks ipratropium bromide its FEV1 of 40 micrograms and FVC every day for 4 times, peak value and average all have remarkable rising, patient's expiratory dyspnea symptom is obviously improved, curative effect obviously is better than ipratropium bromide and Salmeterol, untoward reaction is few, modal untoward reaction is dry and cough, most of patients continues the treatment transference cure, needn't therapy discontinued, adverse reaction rate and severity are not dose-dependently and change.
Seven, the benefit of the hydrolysis reaction of Scopolamine generation of the present invention and traditional hydrolysis reaction relatively
The present invention adopts microwave technology to prepare scopine, prepares scopine relatively with traditional Scopolamine hydrolysis reaction, and the reaction times shortens 60 times, and yield improves 25%, and side reaction product reduces 10 times.
Eight, the replacement linked reaction that takes place of halogenide of the present invention and ester and the classical inverse benefit comparison of answering
The present invention adopts ultrasonic technology to prepare thiophene ethanol acid methyl esters, should compare with classical inverse, and the reaction times shortens 20 times, and yield improves 1 times.
Nine, condensation reaction of the present invention and the classical inverse benefit of answering relatively
The condensation reaction that the present invention adopts microwave technology that scopine and thiophene ethanol acid methyl esters are taken place should be compared with classical inverse, and the reaction times shortens 50 times, and yield improves 1 times.
The Figure of description explanation
Fig. 1. the thiatro bromoaminium anhydrous compound synthetic route chart
Fig. 2. the thiatro bromoaminium anhydrous compound synthesis process flow diagram
Fig. 2 a. hydrolysis reaction process route chart
Two (2-thienyl) methyl glycolate (intermediate two) the preparation technology's schemas of Fig. 2 b.
Two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester (intermediate three) the preparation technology's schemas of Fig. 2 c.
Fig. 2 d. tiotropium bromide crude product preparation were established figure
Fig. 2 e. tiotropium bromide process for refining route map
Claims (6)
1. method for preparing tiotropium bromide, it is characterized in that it is that the hydrolysis reaction of scopolamine hydrobromide under microwave action prepares intermediate one, bromo thiophene and magnesium and the dimethyl oxalate replacement linked reaction under the ultrasonic wave effect prepares intermediate two, the intermediate three of intermediate one and the condensation reaction preparation of intermediate two under microwave action prepares chemical name through crystallization and recrystallization process again after bromination reaction prepares the tiotropium bromide crude product be 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, molecular formula is C
19H
22BrNO
4S
2, molecular weight is 472.42, structural formula is
The end product thiatro bromoaminium anhydrous compound, the title of described intermediate one, intermediate two, intermediate three is respectively scopine, two (2-thienyl) methyl glycolate, two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester, their structural formula is respectively
Intermediate one intermediate two intermediates three.
2. the described method for preparing tiotropium bromide of claim 1, it is characterized in that preparing the used intermediate of end product thiatro bromoaminium anhydrous compound one is by getting scopolamine hydrobromide, methyl alcohol, salt of wormwood, putting airtight wavelength is in the microwave normal pressure reactor of 0.1～100cm, under the room temperature condition after the rapid reaction, evaporated under reduced pressure, add methylene chloride, filter, filter cake is given a baby a bath on the third day after its birth inferior with methylene dichloride, merging filtrate, anhydrous sodium sulfate drying, evaporated under reduced pressure, get scopine oily matter, i.e. the method for intermediate one preparation.
3. the described method for preparing tiotropium bromide of claim 1, it is characterized in that preparing the used intermediate of end product thiatro bromoaminium anhydrous compound two is by getting bromo thiophene, magnesium chips, dimethyl oxalate, ether, put in the ultrasound reactor that frequency is 20～300KHZ, under the room temperature condition after the rapid reaction, in reaction solution, drip dilute sulphuric acid, tell the ether layer, wash with aqueous sodium carbonate, washing, anhydrous sodium sulfate drying, evaporate to dryness is used the toluene recrystallization, get two (2-thienyl) methyl glycolate crystallisates, i.e. the method for intermediate two preparation.
4. the described method for preparing tiotropium bromide of claim 1, it is characterized in that preparing the used intermediate of end product thiatro bromoaminium anhydrous compound three and be intermediate two and intermediate one mixing by mole molecular ratios such as getting, adding the rearmounted airtight wavelength of sodium is in 0.1～100cm microwave normal pressure reactor, under the room temperature condition after the rapid reaction, in reaction solution, add toluene, continue reaction, add the ethyl acetate dilution, water washing organic layer 2 times, anhydrous sodium sulfate drying filters, evaporate to dryness, use the acetonitrile recrystallization, get two (2-thienyl) oxyacetic acid Rhizome of Japanese Scopolia ester crystallisates, i.e. the method for intermediate three preparation.
5. the described method for preparing tiotropium bromide of claim 1, it is characterized in that preparing the tiotropium bromide crude product is by getting the solution that intermediate three is dissolved in anhydrous methylene chloride and anhydrous acetonitrile, cooling, getting cold acetonitrile joins in the monobromethane that is chilled to same temperature, join in the solution that fills anhydrous methylene chloride and anhydrous acetonitrile, airtight, rise to room temperature reaction, filter, the method preparation of tiotropium bromide crude product.
6. the described method for preparing tiotropium bromide of claim 1, it is characterized in that the thiatro bromoaminium anhydrous compound highly finished product are by getting the tiotropium bromide crude product, with twice in acetonitrile-methanol solution, gac recrystallization, add ether in the recrystallization liquid and separate out crystallization, filter, vacuum-drying, the method preparation of thiatro bromoaminium anhydrous compound highly finished product.
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| CN2008100810198A CN101230063B (en) | 2008-02-20 | 2008-02-20 | Method for preparing tiotropium bromide |
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| CN101768158B (en) * | 2010-01-04 | 2013-05-29 | 南昌弘益科技有限公司 | Tiotropium bromide anhydride and preparation method thereof |
| CN102146079B (en) * | 2011-02-28 | 2013-02-13 | 广州瑞尔医药科技有限公司 | Preparation method of scopolamine butylbromide |
| CZ304808B6 (en) * | 2012-03-16 | 2014-11-05 | Zentiva, K.S. | Process for preparing scopine ester of di-(2- thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide and a new form thereof |
| CN103880837A (en) * | 2014-03-27 | 2014-06-25 | 张家港威胜生物医药有限公司 | Synthetic method of cimetropium bromide |
| CN113264929B (en) * | 2021-05-02 | 2023-10-10 | 润生药业有限公司 | Preparation method of tiotropium bromide |
| CN114213408B (en) * | 2021-12-15 | 2023-03-31 | 台州仙琚药业有限公司 | Preparation method of tiotropium bromide |
| CN114088846A (en) * | 2022-01-19 | 2022-02-25 | 深圳市海滨制药有限公司 | Detection method of scopine and impurities thereof |
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| CN1861598A (en) * | 2006-03-07 | 2006-11-15 | 南昌弘益科技有限公司 | Preparation process of thiatro bromoaminium anhydrous compound |
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| CN101863885A (en) * | 2010-06-03 | 2010-10-20 | 南京金丹呈医药技术有限公司 | Method for preparing tiotropium bromide |
| CN101863885B (en) * | 2010-06-03 | 2012-05-30 | 南京金丹呈医药技术有限公司 | Preparation method of tiotropium bromide |
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