CN110294680A - A kind of preparation method in levels Moses spit of fland - Google Patents
A kind of preparation method in levels Moses spit of fland Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The present invention relates to field of medicinal chemistry, provide a kind of preparation method in levels Moses spit of fland, aromatic nucleophilic substitution reaction occurs by starting material and o-fluorotobuene of N- methyl -3- hydroxyl-amphetamine, then obtains levels Moses spit of fland at salt through (S)-MA chiral resolution.Multistep reaction use continuous operation in the route, post-reaction treatment extraction and chiral resolution are all made of methyl tertiary butyl ether(MTBE) at salt solvent, post-process without decompression and concentration operation and anhydrous sodium sulfate drying steps, it is easy to operate, total recovery reaches 20%-25%, and 99.5% or more purity meets related quality criterion.The technique is without special reaction parameter and equipment requirement, and high income, by-product are few, post-processing is simple, and reaction yield is high, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method in levels Moses spit of fland.
Background technique
Levels Moses spit of fland, chemical name are as follows: (R)-N- methyl -3- (2- methylphenoxy) -3- phenylpropyl amine hydrochlorate,
Trade name: STRATTERA.Bayer Pharmaceuticals Corp's exploitation, in November, 2002 is by U.S. FDA (Food and drug
Administration) approval listing, suitable for 6 years old and the treatment of the above children ADHD (ADHD) patient；2004 Nian Youou
Continent drug administration (EMA) approval listing, for treating children ADHD.
Levels Moses spit of fland, (R)-(-) enantiomter of atomoxetine, be a kind of selective norepinephrine again
Uptake inhibitor, specifically with flowering structure:
Atomoxetine Hydrochloride
The synthetic route in levels Moses spit of fland is numerous, such as: original grinds patent US4018895/US4314081 with 3- first ammonia
Base -1- phenyl -1- propanone hydrochloride through sodium hydroxide solution salt at free alkali, after it restored with borine generate 3- (methylamino) -
1- phenyl propanol generates 3- methylamino -1- phenyl-n-propyl chloride to its nucleophilic displacement of fluorine with thionyl chloride, finally and o-methyl-benzene
Phenol occurs alkylation and generates racemic tomoxetine.The route is longer, and is directed to using unstable borine, and finished product is not yet
Chiral fractionation needs further chiral resolution to obtain levels Moses spit of fland.
U.S.'s original grinds US4018895/US4314081 using the chloro- 3- phenyl-propane of 1- as starting material, with N- bromo succinyl
Imines occurs bromo and removes the succimide group generation bromo- 3- phenyl-n-propyl chloride of 3-, and nucleophilic occurs with ortho-methyl phenol
Racemic tomoxetine is generated through methylamine nucleophilic displacement of fluorine after substitution, needs further chiral resolution.It can obtain levels Moses
Spit of fland.Nucleophilic substitution step occurs for this method and ortho-methyl phenol, can generate chlorine and replace impurity, and the route is too long, uncomfortable
Suitable industrialized production.
European patent EP 0052492 is put forward for the first time atomoxetine synthetic method, medicinal effectiveness be racemic modification support not
2 times of Xi Ting are 9 times of (S)-atomoxetine.This method is with N, N- dimethyl -3- (2- methylphenoxy)-amphetamine
N- methyl-esterified reaction occurs for beginning raw material and phenyl chloroformate, then through being deprotected, chiral resolution obtains levels Moses at salt
Spit of fland.The used starting material of the route is difficult to obtain, and N- methyl is also easy to produce and eliminates two by-products, and reaction is not easy to control.
Aldrich patent US4868344 is using 3- chloro-benzene acetone as starting material, chiral diisopinocampheylchloroborane base chlorine boron
Alkane asymmetric reduction generates band chiral intermediate, wherein if wherein mesosome is S type, then is turned into through Mitsunobe reaction chirality
(R) type intermediate；This then directly generates (R) type intermediate with ortho-methyl phenol as (R) type.The chiral intermediate then generated
Chlorine replaces through methylamine generates atomoxetine.This method raw material availability is high, can be directly via in asymmetric reaction preparation chirality
Mesosome, thus the chiral finished product of reacted preparation again.The disadvantage is that this chiral reducing agent price is higher, and because reduction is not thorough
It might have more racemic modification residual, be not suitable for industrialized production.
Original grinds patent US6008412 using N- methyl -3- hydroxyl-amphetamine as starting material, first through (S)-mandelic acid into
Row chemical chiral resolution, solution removes mandelate in gained intermediate alkali sodium hydroxide aqueous solution, free alkali again with o-fluorotobuene
Aromatic nucleophilic substitution reaction occurs under the conditions of high-temperature alkaline and obtains atomoxetine free base, logical hydrogen chloride gas obtain hydrochloride Ah
Atomoxetine.In the technique it is chiral split obtained single configuration intermediate with o-fluorotobuene reaction step, reaction condition
Racemization can occur under high temperature strong alkaline condition, isomer impurities content increases, and optical purity of products reduces, subsequent purification step
Rapid purification difficult.
Original grinds patent US6541668/WO0061540 using N- methyl -3- hydroxyl-amphetamine as starting material and o-fluorotobuene
Aromatic nucleophilic substitution reaction occurs first, then is solved salt under alkaline condition at salt through (S)-mandelic acid chiral resolution, leads to hydrogen chloride gas
Levels Moses spit of fland is obtained at salt.The technique first carries out nucleophilic aromatic substitution step, then chiral fractionation, avoids high-temperature alkali
Property under the conditions of racemization risk occurs, inventor carries out process optimization on the basis of with reference to this route, obtains satisfaction industrialization
The Atomoxetine hydrochloride production technology of production.
Summary of the invention
In view of above-mentioned complex process, and plurality of impurities is easy to produce in technical process, technique is time-consuming and post-processing is cumbersome, hair
Bright people is derived from the theory of design on the basis of reference United States Patent (USP) US6541668/WO0061540 based on quality, by a large amount of real
It tests, explores a kind of preparation method in more efficient levels Moses spit of fland, this method is easy to operate, and product yield is high, optics
Purity and product quality meet related quality criterion, and process stabilizing is suitble to industrialized production.
The technical solution adopted by the invention is as follows:
A kind of preparation method of tomoxetine hydrochloride, it is characterised in that itself the following steps are included:
1) 3- (methylamino) -1- phenyl propanol and alkali at room temperature, are added to stirring and dissolving in reaction dissolvent, it is backward above-mentioned
O-fluorotobuene high temperature is added in mixed liquor, aromatic nucleophilic substitution reaction occurs；Water, methyl tertiary butyl ether(MTBE) extraction are added after reaction
It takes, purify water washing, retain methyl tertiary butyl ether(MTBE) organic phase solution；
2) ethyl acetate is added into the t-butyl methyl ether solution that step 1) obtains, (S)-almond is added in stirring heating
Acid is added crystal seed insulated and stirred crystallization, obtains (R)-atomoxetine mandelate；
3) (R)-atomoxetine mandelate is solved in the case where percent by volume is 30% sodium hydrate aqueous solution alkaline condition
Salt, logical hydrogen chloride gas obtain tomoxetine hydrochloride crude product；
4) it is carried out being recrystallized to give tomoxetine hydrochloride with dehydrated alcohol.
Preferably 110~120 DEG C of reaction temperature described in step 1) described above.
The preferred DMSO of reaction dissolvent described in step 1) described above.
Alkali used in reaction described in step 1) described above is sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, the preferably tert-butyl alcohol
Potassium.
Potassium tert-butoxide dosage used in step 1) described above is 1.1~2.0 equivalents, preferably 1.3-1.4 equivalent.
Reaction described in step 1) described above (S)-mandelic acid dosage is 0.4~0.8 equivalent.It is preferred that 0.4-0.5 works as
Amount.
Reaction temperature described in step 2) described above is preferably 40~45 DEG C.
The temperature of the logical hydrogen chloride gas of reaction described in step 3) described above is 0~15 DEG C, preferably 0~5 DEG C.
Reaction described in step 3) described above leads to hydrogen chloride gas to reaction system to pH2~3, stops ventilation.
Innovation of the present invention:
Technique finishing time length, the low efficiency that prior art United States Patent (USP) US6541668/WO0061540 is introduced, are related to
It is repeatedly concentrated under reduced pressure and the dry post-processing operation of anhydrous sodium sulfate, total recovery 10-15%, yield is relatively low.Exist for the technique
The problem of, the present invention improves technique referring to the above method, will be fragrant specially in the synthetic route of levels Moses spit of fland
Fragrant nucleophilic substitution is operated continuously with chemical chiral resolution step, which selects methyl tertiary butyl ether(MTBE) extraction
Solvent is taken, (S)-mandelic acid is added directly into the methyl tertiary butyl ether(MTBE) organic phase solution obtained through extracting operation and carries out chirality
It splits, reduced pressure and anhydrous sodium sulfate drying process is reduced compared with patent, reduces consumption of organic solvent, substantially shortens
Finishing time reduces energy consumption and human cost.In addition, the reaction time substantially shortens, by patent by increasing base amount
It foreshortens to 5-6 hours within 20 hours in US6541668/WO0061540, it can fully reacting.Intermediate mandelic acid atropic Moses
It is dense to reduce solvent after understanding salt equally using methyl tertiary butyl ether(MTBE) as reaction dissolvent for spit of fland alkaline condition solution salt and the operation of synthetic hydrochloric acid salt
Contracting and anhydrous sodium sulfate drying process, organic solvent are fully used, and significantly reduce the output of industrial consumption energy and the three wastes.
15 feather weight process certifications work is completed in the present invention at present, meets industrial mass production demand, while different after purification
Structure body content is lower than 0.05%, and route total recovery reaches 20%-25%, and 99.5% or more purity meets related quality criterion.
For the technique without especial equipment requirements, no special reaction parameter is easy to operate, while improving finished product yield, produces
Quality meets related quality criterion, is suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction pattern of embodiment 1.
Specific embodiment
Below with reference to test example and specific embodiment, the present invention is described in further detail.But this should not be understood
It is only limitted to embodiment below to invent the range of above-mentioned theme, it is all that this hair is belonged to based on the technology that the content of present invention is realized
Bright range.
Embodiment 1:
At room temperature, by 37.16kg (224.9mol) N- methyl -3- hydroxyl-amphetamine and 34.66kg (308.8mol) tertiary fourth
Potassium alcoholate, which is added to, stirs and is warming up to 110~120 DEG C in 109.88kg DMSO, 74.30kg is added in Xiang Shangshu mixed liquor
(674.7mol) o-fluorotobuene insulated and stirred is reacted 5-6 hours.74.06kg purified water is added into reaction solution after reaction,
55.64kg methyl tertiary butyl ether(MTBE) extracts liquid separation, and water phase extracts liquid separation with 55.45kg MTBE, merges organic phase, and 74.84kg is added
Purifying washing organic phase solution, liquid separation retain methyl tertiary butyl ether(MTBE) organic phase solution.
55.46kg methyl tertiary butyl ether(MTBE) is added into above-mentioned methyl tertiary butyl ether(MTBE) organic solution, stirring is warming up to 40~45
DEG C, 15.35kg (100.9mol) (S)-mandelic acid is added, 37.21g atomoxetine mandelate crystalline substance is added after stirring 15min
Kind, 40-45 DEG C of stirring and crystallizing of temperature control 2 hours, then it is naturally cooling to 0~5 DEG C of stirring and crystallizing 6-8h, it is centrifuged, filter cake 27.81kg
Methyl tertiary butyl ether(MTBE) elution, it is dry, obtain 31.40kg (R)-atomoxetine mandelate, yield 34.4%, related material purity
99.40%.(note: since the intermediate is (R)-atomoxetine mandelate, then this does not do nuclear-magnetism structure elucidation)
31.21kg (76.6mol) (R)-atomoxetine mandelate is added to 115.62kg MTBE and 66.09kg
In the mixed liquor of purified water, 30% sodium hydrate aqueous solution of 16.02kg is added dropwise, drop finishes, and stirs 1 hour after reaction solution clarification.Point
Liquid, water phase are added 46.13kg MTBE and extract liquid separation, merge organic phase, and 66.08kg is added to purify water washing, and liquid separation retains organic
Phase solution.Methyl tertiary butyl ether(MTBE) organic solution is cooled to 0~5 DEG C, hydrogen chloride gas is led into solution to pH=2-3, stopping is ventilated,
There are a large amount of white solids to be precipitated in the process, 0-5 DEG C of temperature control is stirred 2 hours, and centrifugation is dried to obtain levels Moses spit of fland crude product
21.30kg, yield 95.3%, related material purity 99.44%, isomer impurities 3.18%.
21.02kg72.0mol) levels Moses spit of fland crude product is added in 50.31kg dehydrated alcohol, it is warming up to 65~
70 DEG C of dissolutions are stirred 1 hour, and 50-55 DEG C of stirring and crystallizing of temperature control 2 hours is cooled to 0-10 DEG C of stirring and crystallizing 4-6 hours, centrifugation,
8.25kg dehydrated alcohol elutes filter cake, dry white crystals sprills levels Moses spit of fland 17.31kg, yield 82.4%,
Related material purity 99.86%, isomer impurities 0.01%, specific rotation -41.64.
The atomoxetine compound is in X-ray powder diffraction pattern 8.5, and 13.3,13.7,14.7,17.3,22.3,22.6,
There is absorption peak at 24.0,26.4,27.3,29.3 and 29.8 ± 0.2 degree of 2 θ (see Fig. 1)
1HNMR(400MHz,CDCl3)δ:2.293(s,3H,ArCH3),2.397-2.531(m,2H,NHCH2CH2),2.568
(s,3H,NHC H3),3.082-3.135(m,2H,NHCH2),5.372(t,1H,ArOCH),6.577-7.335(m,9H,ArH),
9.642(brs,1H,NH).13C-NMR(100Hz,CDCl3)δ:155.16,140.03,130.46,128.63,128.01,
126.84,126.39,125.70,120.67,112.95,76.33,46.21,34.59,32.80,18.36。
Comparative example 1:(US6541668/WO0061540)
The present inventor's referenced patent method US6541668/WO0061540 has synthesized levels Moses spit of fland, specific as follows:
(1) aromatic nucleophilic substitution reaction: under nitrogen protection, under the conditions of 20-30 DEG C of room temperature is protected from light, by 30.01g
(181.6mmol) N- methyl -3- hydroxyl-amphetamine, 19.44g (199.8mmol) sodium tert-butoxide, 60.01g (544.8mmol) are adjacent
Toluene fluoride is added sequentially to 75mL1, and in 3- dimethyl-imidazolinone solvent, reaction solution stirring is warming up to 110-120 DEG C, stirring 20
Hour, reaction solution is orange transparent, stops heating, and 90ml purified water and 90ml are added into reaction solution to 25-30 DEG C for slow cooling
Toluene stirs 30 minutes, stands liquid separation, and water phase is extracted with 30ml toluene, merges organic phase, purifies water washing organic phase with 90ml
Solution, reduced pressure divide exactly toluene to residue about 30ml, are cooled to 40-50 DEG C, addition 135ml ethyl acetate dilute reaction solution,
13.82g (90.8mmol) (S)-mandelic acid is added into reaction solution, temperature control stirring 2 hours, is cooled to for 40-50 DEG C of temperature control of stirring
0-5 DEG C, there is solid precipitation, temperature control stirring 1 hour, filter, filter cake is eluted with 60ml ethyl acetate, dry white solid of weighing to obtain
Powder 19.31g, yield 26.1%, content of isomer 5.76%.
(2) solve salt synthetic hydrochloric acid salt: by 13.08g (32.1mmol) above-mentioned sample, 40ml50% sodium hydrate aqueous solution according to
It is secondary to be added in 42mL methyl tert-butyl ether solvent, 40 DEG C of -45 DEG C of stirring and dissolvings are warming up to, temperature control stirring 1 hour, stop adding
Heat is down to room temperature, stratification, and water phase is extracted with 26ml methyl tertiary butyl ether(MTBE), merges organic phase, then add into organic phase solution
Enter the dilution of 50ml methyl tertiary butyl ether(MTBE), 23ml isopropanol, stirring are added into residue for vacuum distillation solvent to residue about 60g
3.33g concentrated hydrochloric acid is added, 20-25 DEG C of temperature control is stirred to react 3 hours, filters, with 20mL, methyl tert-butyl ether solvent elution filter
Cake, it is dry, obtain product 7.26g, yield 77.5%, chiral purity 6.32%.
Claims (3)
1. a kind of preparation method in levels Moses spit of fland, it is characterised in that itself the following steps are included:
1) N- methyl -3- hydroxyl-amphetamine and alkali at room temperature, are added to stirring and dissolving in reaction dissolvent, backward above-mentioned mixing
O-fluorotobuene high temperature is added in liquid, aromatic nucleophilic substitution reaction occurs；Water is added after reaction, methyl tertiary butyl ether(MTBE) extracts, is pure
Change water washing, retains methyl tertiary butyl ether(MTBE) organic phase solution；
2) methyl tertiary butyl ether(MTBE) is added into the organic phase solution that step 1) obtains, (S)-mandelic acid, heat preservation is added in stirring heating
Stirring and crystallizing obtains atomoxetine mandelate；
3) atomoxetine mandelate solves salt in the case where mass percent is 30% sodium hydrate aqueous solution alkaline condition, leads to salt
Acid gas obtains tomoxetine hydrochloride crude product；
4) it is carried out being recrystallized to give tomoxetine hydrochloride with dehydrated alcohol.
2. preparation method as described in claim 1, reaction temperature described in step 1) is 100~150 DEG C；Described in step 1)
Reaction dissolvent is dimethyl sulfoxide；Step 1) the alkali is sodium hydroxide, sodium tert-butoxide or potassium tert-butoxide；It is anti-described in step 1)
The molar equivalent for answering alkali used is 1.1~2.0；Reaction described in step 1) (S)-mandelic acid mole dosage is 0.4~0.6；
Reaction temperature described in step 1) is 40~45 DEG C；Reaction-crystallization temperature described in step 2) is 40-45 DEG C, and heat preservation crystallization 2 is small
When, then it is cooled to 0-10 DEG C of crystallization 6-8 hours；The temperature of the logical hydrogen chloride gas of reaction described in step 3) is 0~20 DEG C；Step 3) institute
It is ventilation terminal that hydrogen chloride gas to system pH1~4 are led in the reaction stated.
3. preparation method as claimed in claim 2, reaction temperature described in step 1) is 110~120 DEG C；Described in step 1)
Reaction dissolvent is dimethyl sulfoxide；Step 1) the alkali is potassium tert-butoxide；The institute's alkali charge of reaction described in step 1) is 1.3-1.4
Molar equivalent；Reaction described in step 1) (S)-mandelic acid dosage is 0.4-0.5 molar equivalent；Reaction described in step 3) is logical
The temperature of hydrogen chloride gas is 0-5 DEG C；It is reaction end that hydrogen chloride gas to system pH2~3 are led in reaction described in step 3).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527114A (en) * | 2021-06-15 | 2021-10-22 | 海南卓科制药有限公司 | Preparation method of tomoxetine hydrochloride |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0052492A1 (en) * | 1980-11-14 | 1982-05-26 | Eli Lilly And Company | 3-Aryloxy-3-phenylpropylamines |
| CN1275077A (en) * | 1997-10-14 | 2000-11-29 | 伊莱利利公司 | Process to make chiral compound |
| US6541668B1 (en) * | 1999-04-09 | 2003-04-01 | Eli Lilly And Company | Methods for preparing 3-arloxy-3-arylpropylamines and intermediates thereof |
| CN1942429A (en) * | 2004-06-28 | 2007-04-04 | 特瓦药物精化学品股份有限公司 | Processes for the preparation of tomoxetine |
| CN101400644A (en) * | 2005-09-07 | 2009-04-01 | 特瓦药物精化学品股份有限公司 | Processes for the preparation of atomoxetine hydrochloride |
-
2018
- 2018-03-22 CN CN201810238323.2A patent/CN110294680A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0052492A1 (en) * | 1980-11-14 | 1982-05-26 | Eli Lilly And Company | 3-Aryloxy-3-phenylpropylamines |
| CN1275077A (en) * | 1997-10-14 | 2000-11-29 | 伊莱利利公司 | Process to make chiral compound |
| US6541668B1 (en) * | 1999-04-09 | 2003-04-01 | Eli Lilly And Company | Methods for preparing 3-arloxy-3-arylpropylamines and intermediates thereof |
| CN1942429A (en) * | 2004-06-28 | 2007-04-04 | 特瓦药物精化学品股份有限公司 | Processes for the preparation of tomoxetine |
| CN101400644A (en) * | 2005-09-07 | 2009-04-01 | 特瓦药物精化学品股份有限公司 | Processes for the preparation of atomoxetine hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527114A (en) * | 2021-06-15 | 2021-10-22 | 海南卓科制药有限公司 | Preparation method of tomoxetine hydrochloride |
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Address after: No.10 building, Zhengzhou Lingkong biomedical park, northeast corner of the intersection of Huanghai Road and biotechnology 2nd Street, Zhengzhou Airport Economic Comprehensive Experimental Zone, Zhengzhou City, Henan Province Applicant after: Zhengzhou shenlanhai Biomedical Technology Co.,Ltd. Address before: 100083 Beijing city Haidian District Qinghua East Road No. 16 building 1401 yearhigh Applicant before: BEIJING SHENLANHAI BIOLOGICAL MEDICINE TECHNOLOGY Co.,Ltd. |
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Application publication date: 20191001 |