CN106542973A - Ta Simeiqiong intermediates and preparation method thereof - Google Patents

Ta Simeiqiong intermediates and preparation method thereof Download PDF

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CN106542973A
CN106542973A CN201510591597.6A CN201510591597A CN106542973A CN 106542973 A CN106542973 A CN 106542973A CN 201510591597 A CN201510591597 A CN 201510591597A CN 106542973 A CN106542973 A CN 106542973A
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compound
reaction
potassium
simeiqiong
potassium carbonate
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CN106542973B (en
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包金远
黄辉
蒋玉伟
许毅
侯建
张孝清
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Nanjing Huawe Medicine Technology Development Co Ltd
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Nanjing Huawe Medicine Technology Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Ta Simeiqiong intermediates and preparation method thereof, the present invention obtain compound I with benzyl bromine reaction with compound a as raw material；Then in the presence of the combination catalyst of two combination catalyst or osmium tetroxide, potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and the Methanesulfomides for being hydrated potassium osmate, potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and Methanesulfomide, reaction obtains compound II；Compound II oxidation reactions in the presence of sodium metaperiodate or lead tetraacetate, obtain intermediate compound III, then carry out reduction reaction, obtain compound IV；Compound IV reduction reaction debenzylation protection groups are obtained into compound V, is then reacted with paratoluensulfonyl chloride, is carried out hydroxyl protection, then the cyclization under potassium carbonate effect, obtains Ta Simeiqiong midbody compounds VI.The invention provides new technology prepared by a kind of Ta Simeiqiong intermediates, the good product purity of gained, quality are higher, it is adaptable to industrialized production.

Description

Ta Simeiqiong intermediates and preparation method thereof
Technical field
The invention belongs to organic synthetic route design and its bulk drug and intermediate preparing technical field, more particularly to A kind for the treatment of of insomnia patients medicine Ta Simeiqiong intermediates and preparation method thereof.
Background technology
Ta Simeiqiong (Tasimelteon) is ground by Maryland, US continent Wanda drugmaker (Vanda Pharma) A kind of small molecule melatonin receptors activator sent out, can improve unexpected advanced sleep time person's Sleep latency simultaneously With sleep holding situation.The medicine is listed in the approval of the Jing of in January, 2014 U.S. FDA, and trade name Hetlioz is used In the patient for treating non-24 hours obstacles (Non-24).
Ta Simeiqiong's (Tasimelteon) is chemical entitled：(1R, 2R)-N- [[2- (2,3- dihydro -4- benzofurans Base) cyclopropyl] methyl] propionamide (I), its structural formula is：
Document《Organic Process Research&Development》The 618-620 page of the 5th phase of volume 6 (2002) the 6th the 821-827 page of the phase (2003) of volume and 7 then discloses another kind of chiral synthesis Ta Simeiqiong Method, by 2,3- Dihydro-benzofuran -4- ethene chiral catalyst effect under, carry out first not Asymmetric epoxidation (AE) reacts, then carries out asymmetric dehydroxylation (AD) reaction, and Ta Simeiqiong is finally obtained.
Important intermediates of the compound VII (structural formula is as follows) as Ta Simeiqiong, lacks in prior art The preparation method of the weary intermediate, if easily obtaining the key intermediate VII for preparing Ta Simeiqiong, so as to High-quality Ta Simeiqiong bulk drugs are obtained, is this area technical issues that need to address.
The content of the invention
The invention provides a kind of purity is higher, the synthesis of the shorter Ta Simeiqiong intermediates of process route is newly square Method.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of new synthetic method of Ta Simeiqiong midbody compounds V, synthetic route are as follows：
Comprise the steps：
(1) with compound a, as raw material, the reaction under potassium carbonate effect obtains compound I with benzyl bromine；
(2) compound I is reacted in the presence of catalyst, obtains midbody compound II, described urges Agent is the combination of two hydration potassium osmates, potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and Methanesulfomide Or the combination of osmium tetroxide, potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and Methanesulfomide；
(3) by midbody compound II in the presence of sodium metaperiodate or lead tetraacetate oxidation reaction, in obtaining Intermediate compounds therefor III；Then reduction reaction is carried out in the presence of sodium borohydride or potassium borohydride, obtain chemical combination Thing IV；
(4) by compound IV, in the presence of catalyst, reduction reaction debenzylation protection group obtains compound V.
Further, step (1) is acted in potassium carbonate with benzyl bromine in acetonitrile solvent by raw material of compound a Lower back flow reaction obtains compound I.
In a kind of scheme, step (1) compound a is 1 with the molar ratio of benzyl bromine：1, reaction is obtained Crude product compound I is recrystallized to give in acetonitrile.
Further, the temperature that step (2) is reacted is 25 DEG C, and the solvent of reaction is the mixing of the tert-butyl alcohol and water.
In a kind of scheme, step (2) compound I and two hydration potassium osmate, potassium carbonate, the potassium ferricyanide and The molar ratio of Methanesulfomide is 1：0.005：3：3.
In another kind of scheme, step (2) compound I and osmium tetroxide, potassium carbonate, the potassium ferricyanide and first The molar ratio of sulfonamide is 1：0.005：3：3, the temperature of reaction is 25 DEG C, and the time of reaction is 12h, The crude product that post processing is obtained is recrystallized in ethyl acetate.
Further, the temperature of step (3) oxidation reaction is 0～5 DEG C, and the solvent of reaction is tetrahydrofuran.
Further, the molar ratio of step (3) meso-periodic acid sodium or lead tetraacetate and compound II be 2～ 2.5：1.
Further, in step (3), the temperature of reduction reaction is 0～15 DEG C, reacts the crude product for obtaining in second Recrystallize in acetoacetic ester and petroleum ether mixed solvent.
Further, in step (4), the catalyst of reduction reaction is concentrated hydrochloric acid, trifluoroacetic acid or boron chloride.
Further, in step (4) reduction reaction be hydrogenating reduction, catalyst be palladium carbon/hydrogen, palladium bichloride/ Any one in hydrogen or Raney's nickel/hydrogen, the pressure of hydrogenation reaction is 0.2～0.5MPa, and the temperature of reaction is 25～40 DEG C.
In a kind of scheme, in step (4), the catalyst of hydrogenation reduction is palladium carbon, the pressure of hydrogenation reaction Power is 0.3MPa, and the temperature of reaction is 30 DEG C, and the post-treated crude product for obtaining is recrystallized in acetonitrile.
Present invention also offers the method that compound VII is prepared by compound V, but it is not limited only to this side Case：By compound V and paratoluensulfonyl chloride reaction, hydroxyl protection is carried out, then the cyclization under potassium carbonate effect, Midbody compound VI is obtained, its reaction equation is as follows.
The present invention also aims to a kind of new intermediate compound IV for preparing Ta Simeiqiong is provided, its knot Structure formula is as follows：
In a kind of scheme, midbody compound II is added in tetrahydrofuran solvent sodium metaperiodate catalyst, 0～5 DEG C carries out oxidation reaction, obtains intermediate compound III；Then sodium borohydride effect under 0～15 DEG C enter Row reduction reaction, obtains compound IV crude products, is recrystallized to give in ethyl acetate and petroleum ether mixed solvent Compound IV.
The present invention obtains compound I with benzyl bromine reaction with compound a as raw material；Then two be hydrated potassium osmates, The combination catalyst or osmium tetroxide of potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and Methanesulfomide, React in the presence of the combination catalyst of potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and Methanesulfomide To compound II；Compound II oxidation reactions in the presence of sodium metaperiodate or lead tetraacetate, obtain intermediate Compound III, then reduction reaction is carried out, obtain compound IV；Compound IV reduction reactions debenzylation is protected Base obtains compound V, then reacts with paratoluensulfonyl chloride, carries out hydroxyl protection, then acts in potassium carbonate Lower cyclization, obtains Ta Simeiqiong midbody compounds VI.The invention provides prepared by a kind of Ta Simeiqiong intermediates New technology, the good product purity of gained, quality are higher, it is adaptable to industrialized production.
Specific embodiment
For ease of understanding, below the present invention will be described in detail by specific embodiment.Need special , it is noted that specific embodiment is merely to explanation, it is clear that one of ordinary skill in the art can be according to herein Illustrate, make various amendments within the scope of the present invention to the present invention.
Embodiment 1：The synthesis of intermediate compound I
Molecular weight Inventory Molal quantity/mol Equivalent
5,8- dihydros naphthols (a) 146 2.5kg 17.1 1
Acetonitrile 40 17L
Potassium carbonate 138 2.36kg 17.1 1
Benzyl bromine 171 2.93kg 17.1 1
Ethyl acetate 1L
2.5kg raw material a and 15L acetonitriles are added in 20L reactors, after stirring and dissolving, 2.36kg is added Potassium carbonate, nitrogen protection is lower to add 2.93kg benzyl bromines, is warming up to back flow reaction 12h.After being cooled to room temperature, take out Filter, filter cake are washed with 1L ethyl acetate, filtrate concentration, obtain brown oil.2L is added in concentrate Acetonitrile, is warming up to and is refluxed 2h.Room temperature is cooled to, 0 DEG C is further cooled to, is continued stirring 2h, is taken out Filter, filter cake are washed with the cold acetonitriles of 200mL, and the forced air drying 24h at 35 DEG C obtains 2.1kg brown solids, That is compound I, yield 50%.
HPLC purity is 99.5%, MS (ESI+, m/z):237.2(M+1).
Embodiment 2：The synthesis of intermediate II
Molecular weight Inventory Molal quantity/mol Equivalent
I 236 2kg 8.5 1
Two hydration potassium osmates 368 14g 0.038 0.5%
Potassium carbonate 138 3.48kg 25.2 3
The potassium ferricyanide 329 8.44kg 25.6 3
The tert-butyl alcohol 20L
Water 120L
Benzyltriethylammoinium chloride 100g
Methanesulfomide 95 814g 8.5 1
Ethyl acetate 18L
The 8.44kg potassium ferricyanides and 20L water are added in 100L kettles, after stirring, 3.48kg carbon is added Sour potassium, the hydration potassium osmates of 14g bis-, the 20L tert-butyl alcohols, 100g benzyltriethylammoinium chlorides and 814g first sulphurs Acid amides, after stirring, adds intermediate compound I, reacts 16h at 25 DEG C.40L water is added, 2h is stirred, Suction filtration, filter cake are colourless to filter liquor with 70L water washings, the forced air drying at 60 DEG C, obtain gray solid.
Above-mentioned solid is added in 20L reactors, adds 18L ethyl acetate, temperature rising reflux to stir 2h, from After being so cooled to room temperature, suction filtration, filter cake are washed with a small amount of ethyl acetate, and forced air drying at 60 DEG C obtains 1.8kg Pale solid, i.e. compound II, yield 79%.
HPLC purity is 99.6%, MS (ESI+, m/z):271.2(M+1).
Embodiment 3：The synthesis of intermediate II
Molecular weight Inventory Molal quantity/mol Equivalent
I 236 2kg 8.5 1
Osmium tetroxide 254.2 10.8g 0.038 0.5%
Potassium carbonate 138 3.48kg 25.2 3
The potassium ferricyanide 329 8.44kg 25.6 3
The tert-butyl alcohol 20L
Water 120L
Benzyltriethylammoinium chloride 100g
Methanesulfomide 95 814g 8.5 1
Ethyl acetate 18L
The 8.44kg potassium ferricyanides and 20L water are added in 100L kettles, after stirring, 3.48kg carbon is added Sour potassium, 10.8g osmium tetroxides, the 20L tert-butyl alcohols, 100g benzyltriethylammoinium chlorides and 814g methylsulfonyls Amine, after stirring, adds intermediate compound I, reacts 12h at 25 DEG C.40L water is added, 0.5h is stirred, Suction filtration, filter cake are colourless to filtrate with 70L water washings, the forced air drying at 60 DEG C, obtain gray solid.
Above-mentioned solid is added in 20L reactors, 18L ethyl acetate is added, temperature rising reflux stirring 2h is cold But to room temperature, suction filtration, filter cake are washed with a small amount of ethyl acetate, and forced air drying at 60 DEG C obtains 1.73kg grey White solid, yield 75%.HPLC purity is 99.1%.
Embodiment 4：The synthesis of intermediate III
Molecular weight Inventory Molal quantity/mol Equivalent
II 270 3.8kg 14 1
THF 30L
H2O 9+64L
NaIO4 214 7.6kg 35.5 2.5
EA 64L
Saturated sodium-chloride 36L
Anhydrous sodium sulfate 10kg
In 50L kettles, add 3.8kg intermediate IIs, 30L tetrahydrofurans and 9L water, nitrogen protection to decline Temperature adds 7.6kg sodium metaperiodates, finishes insulation reaction 2.5h to 0 DEG C.TLC shows that raw material fundamental reaction is complete Quan Hou, suction filtration, filter cake 20L ethyl acetate drip washing, filtrate are proceeded in 100L reactors, add 20L second Acetoacetic ester, 30L water, stirring point liquid, water are mutually extracted once with 30L ethyl acetate again, merge organic phase, then Washed once with 20L saturated nacl aqueous solutions, add 5kg anhydrous sodium sulfate dryings 1h.Suction filtration, filtrate in At 40 DEG C, lucifuge concentration, obtains brown oil and casts single step reaction immediately.
Embodiment 5：The synthesis of intermediate III
Molecular weight Inventory Molal quantity/mol Equivalent
II 270 3.8kg 14.07 1
Dichloromethane 70L
Lead tetraacetate 443.38 6.24kg 14.07 1
Add 6.24kg lead tetraacetates and 40L dichloromethane in 100L kettles, under stirring, be slowly added to 3.8kg thereto The solution that compound II and 30L dichloromethane is made into, reacts 2h at room temperature, is slowly added to 10L after adding Water, suction filtration after stirring 1h, filtrate split-phase, organic phase are washed once with 30L saturated aqueous common salts, anhydrous slufuric acid Sodium is dried, suction filtration, filtrate lucifuge concentration at 35 DEG C, obtains brown oil, puts into next step reaction immediately.
Embodiment 6：The synthesis of intermediate compound IV
Molecular weight Inventory Molal quantity/mol Equivalent
III 270 -
MeOH 38L
NaBH4 1.8kg
Water 60L
38L methyl alcohol is added in 4 gained concentrate of embodiment, 0-10 DEG C is cooled to, is dividedly in some parts sodium borohydride, Control temperature is less than 15 DEG C, adds and reacts 6h after 0 DEG C.60L water, and temperature control are added dropwise in reactant liquor Less than 20 DEG C, after dripping off, continue stirring 0.5h, suction filtration, filter cake 40L water washings, air blast at 50 DEG C are done Dry 24h, obtains silver gray solid 2.7kg.
Above-mentioned solid is added in 20L reactors, is added the stirring of 5L ethyl acetate to be warming up to backflow, 5L is added dropwise Petroleum ether, drips off rear insulated and stirred 1h, continues stirring 2h, suction filtration, a small amount of second of filter cake after being cooled to room temperature Acetoacetic ester/n-hexane (1/2, v/v) mixed solvent drip washing, forced air drying 24h at 45 DEG C, obtains 2.4kg grey Solid, i.e. compound IV, yield 88%, HPLC purity are 99.2%.
1H-NMR (400MHz, DMSO-d6)：δ 7.46 (d, J=7.2Hz, 2H), 7.42-7.38 (m, 2H), 7.34-7.31 (d, J=7.2Hz, 1H), 7.07 (t, J=8.0Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.78 (d, J=7.6Hz, 1H), 5.08 (s, 2H), 4.72-4.69 (m, 2H), 3.59-3.53 (m, 2H), 3.51-3.48 (m, 2H), 2.88 (t, J=7.6Hz, 2H), 2.80 (t, J=7.2Hz, 2H)；13C-NMR (400MHz, DMSO-d6)：δ 156.98,139.61,138.04,128.92,128.10, 127.64,126.99,126.10,122.77,110.21,69.70,62.64,61.13,36.67,30.30； MS(ESI+,m/z)：273.0(M+1).
Embodiment 7：The synthesis of intermediate V
Molecular weight Inventory Molal quantity/mol Equivalent
IV 272 2.4kg 8.8 1
Palladium carbon 220g 9.1%
Methyl alcohol 15L
2.4kg intermediate compound IVs are added in 20L reactors, 15L methyl alcohol, 220g palladium carbons use H2Displacement one In secondary kettle after air, in 0.2MPa H224h is reacted at 30-35 DEG C under pressure.TLC is monitored, reaction knot Shu Hou, suction filtration, filtrate are concentrated in 50 DEG C, and standing cools down to obtain gray solid, and the forced air drying at 40 DEG C is obtained 1.5kg gray solids, yield 94%.
MS(ESI+,m/z):183.3(M+1)。
Embodiment 7：The synthesis of intermediate V
Molecular weight Inventory Molal quantity/mol Equivalent
IV 272 2.4kg 8.8 1
Palladium carbon 220g 9.1%
Methyl alcohol 15L
2.4kg intermediate compound IVs are added in 20L reactors, 15L methyl alcohol, 220g palladium carbons use H2Displacement one In secondary kettle after air, in 0.2MPa H224h is reacted at 30-35 DEG C under pressure.TLC is monitored, reaction knot Shu Hou, suction filtration, filtrate are concentrated in 50 DEG C, and standing cools down to obtain gray solid, and the forced air drying at 40 DEG C is obtained 1.5kg gray solids, yield 94%, MS (ESI+, m/z):183.3(M+1).
Embodiment 8：The synthesis of intermediate V
Molecular weight Inventory Molal quantity/mol Equivalent
IV 272 2.4kg 8.8 1
Palladium carbon 220g 9.1%
Methyl alcohol 15L
2.4kg intermediate compound IVs are added in 20L reactors, 15L methyl alcohol, 220g palladium carbons use H2Displacement one In secondary kettle after air, in 0.3MPa H220h is reacted at 30 DEG C of room temperature under pressure.TLC is monitored, reaction knot Shu Hou, suction filtration, filtrate are concentrated in 50 DEG C, and standing cools down to obtain gray solid, and the forced air drying at 40 DEG C is obtained 1.46kg gray solid.
MS(ESI+,m/z):183.3(M+1).HPLC detects purity 97.9%.
Embodiment 9：The synthesis of intermediate V
Molecular weight Inventory Molal quantity/mol Equivalent
IV 272 2.4kg 8.8 1
Concentrated hydrochloric acid 4.8kg
Methyl alcohol 10L
In 20L reactors, add 2.4kg intermediate compound IVs, 10L methyl alcohol, 4.8kg concentrated hydrochloric acids to be warming up to backflow, Stirring reaction 24h.Concentration boils off most of methyl alcohol, and 10L dichloromethane is added under room temperature, after stirring 30min, Liquid, water is divided to be extracted again once with 2.5L dichloromethane, merging organic phase, 10L saturated common salt water washings, Anhydrous sodium sulfate drying, suction filtration, filtrate are concentrated to dryness, and obtain 1.25kg gray solids, i.e. compound V. MS(ESI+,m/z):183.3(M+1).HPLC detects purity 94.9%.
Embodiment 10：The synthesis of intermediate V
Molecular weight Inventory Molal quantity/mol Equivalent
IV 272 2.4kg 8.8 1
Trifluoroacetic acid 4.8kg
Methyl alcohol 15L
In 20L reactors, add 2.4kg intermediate compound IVs, 10L tetrahydrofurans, 5.0kg trifluoroacetic acids to heat up To backflow, stirring reaction 24h.Concentration boils off solvent, and 10L dichloromethane is added under room temperature, and stirring is lower to be added 5L sodium bicarbonate aqueous solutions, after stirring 30min, point liquid, organic phase use 10L saturated common salt water washings again, Anhydrous sodium sulfate drying, suction filtration, filtrate are concentrated to dryness, and obtain 1.31kg gray solids, i.e. compound V. MS(ESI+,m/z):183.3(M+1)。
Embodiment 11：The synthesis of intermediate V
Molecular weight Inventory Molal quantity/mol Equivalent
IV 272 2.4kg 8.8 1
Boron chloride 117.19 1.55kg 13.2 1.5
Dichloromethane
Tetrabutylammonium iodide 322.37 1.4kg 4.4 0.5
Nitrogen adds 2.4kg intermediate compound IVs, 10L dichloromethane and 1.4kg in 50L reactors under protecting Tetrabutylammonium iodide, stirring are cooled to -40 DEG C, and boron chloride dichloromethane solution (1M, 13.2L) is added dropwise, Rear insulated and stirred 0.5h is dripped off, then is warming up to 0 DEG C of reaction 2h.After reaction terminates, 5L frozen water is added to be quenched instead Should, 5L saturated sodium bicarbonate aqueous solutions are added, after stirring 30min, point liquid, organic phase are full with 10L again And brine It, anhydrous sodium sulfate drying, suction filtration, filtrate be concentrated to dryness, and obtains 1.15kg gray solids, That is compound V.
MS(ESI+,m/z):183.3(M+1)。
Embodiment 12：The synthesis of intermediate VI
Molecular weight Inventory Molal quantity/mol Equivalent
V 182 1.5kg 8.2 1
Pyridine 3.52L
TsCl 190.6 3.24kg 17 2.07
DCM 20.4L
Hydrochloric acid (2mol/L) 12L
Saturated nacl aqueous solution 12L
Methyl alcohol 15L
Ethyl acetate 18L
Potassium carbonate 138 1.29kg 9.3
Anhydrous sodium sulfate 2.5kg
3.24kg paratoluensulfonyl chlorides are dissolved in 4.5L dichloromethane and 0.75L pyridine mixed liquors, in -40 DEG C Under drop to equipped with 1.5kg intermediate V, 3.9L dichloromethane and 2.77L pyridine settled solutions 10L reaction In kettle, not higher than -38 DEG C of control system temperature during dropwise addition.Drop finishes, and 4h, TLC prisons are reacted at -40 DEG C Control.After reaction terminates, 5L dichloromethane and 6L hydrochloric acid (2mol/L) are added, stir 1h.Suction filtration, 5L Eluent methylene chloride filter cake, filtrate point liquid, organic phase use 6L hydrochloric acid (2mol/L) and 6L saturations again successively Sodium chloride solution is washed, organic to be added to 1.5kg anhydrous sodium sulfate dryings 1h, and suction filtration, 2L dichloromethane drench Filter wash cake, 50 DEG C of reduced pressure concentrations of filtrate, obtains brown oil.
To in above-mentioned grease, add 15L methyl alcohol, stirring to be cooled to 0 DEG C.Add 1290g potassium carbonate, stirring Reaction 1h.25 DEG C are warming up to, continue stirring reaction 2h, TLC detections raw material fundamental reaction is complete.Suction filtration, Filter cake takes organic phase with after 10L water and 10L ethyl acetate stirring and dissolvings points of liquid.In addition, filtrate is concentrated, Add 6L water and 6L ethyl acetate extraction point liquid.Merge organic phase, washed with 6L saturated nacl aqueous solutions, 1kg anhydrous sodium sulfate dryings, filter, and 2L ethyl acetate drip washing filter cakes, filtrate are concentrated to give brown oil 2.45kg, i.e. compound VI, yield 93.5%.
HPLC purity is 99.7%, MS (ESI+, m/z):319.5(M+1).
Embodiment 13：The synthesis of intermediate VII
Molecular weight Inventory Molal quantity/mol Equivalent
VI 318 2.45kg 1
Potassium tert-butoxide 112 950g 8.4
THF 36.5L
Saturated nacl aqueous solution 15L
Ethyl acetate 22L
Anhydrous sodium sulfate 2kg
In 100L reactors, compound VI and 36.5L tetrahydrofuran, stirring is added to be cooled to 0 DEG C, temperature control 0-5 DEG C of addition 950g potassium tert-butoxide.Finish, stirring reaction 2h at 0 DEG C, TLC detection raw material fundamental reactions Completely, 9L water and 16L ethyl acetate, stirring point liquid, water layer is added to be extracted with 4L ethyl acetate to reactant liquor Take once, merge organic phase, washed with 15L sodium chloride saturated solutions, 2kg anhydrous sodium sulfate dryings 1h, Suction filtration, 2L ethyl acetate drip washing, filtrate lucifuge reduced pressure concentration at 40 DEG C obtain brown oil.
MS(ESI+,m/z):147.1(M+1)。

Claims (8)

1. a kind of synthetic method of Ta Simeiqiong midbody compounds V, it is characterised in that synthetic route is as follows：
Comprise the steps：
(1) with compound a, as raw material, the reaction under potassium carbonate effect obtains compound I with benzyl bromine；
(2) compound I is reacted in the presence of catalyst, obtains the catalysis described in midbody compound II Agent be the combination of two hydration potassium osmates, potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and Methanesulfomide or The combination of person's osmium tetroxide, potassium carbonate, the potassium ferricyanide, benzyltriethylammoinium chloride and Methanesulfomide；
(3) by midbody compound II in the presence of sodium metaperiodate or lead tetraacetate oxidation reaction, in obtaining Intermediate compounds therefor III；Then reduction reaction is carried out in the presence of sodium borohydride or potassium borohydride, obtain chemical combination Thing IV；
(4) by compound IV, in the presence of catalyst, reduction reaction debenzylation protection group obtains compound V.
2. synthetic method according to claim 1, it is characterised in that step (1) exists by raw material of compound a In acetonitrile solvent, under potassium carbonate effect, back flow reaction obtains compound I with benzyl bromine.
3. synthetic method according to claim 1, it is characterised in that the temperature that step (2) is reacted is 25 DEG C, The solvent of reaction is the mixing of the tert-butyl alcohol and water.
4. synthetic method according to claim 1, it is characterised in that step step (3) meso-periodic acid sodium or four Lead acetate is 2～2.5 with the molar ratio of compound II：1.
5. synthetic method according to claim 1, it is characterised in that the catalyst of reduction reaction in step (4) For concentrated hydrochloric acid, trifluoroacetic acid or boron chloride.
6. synthetic method according to claim 1, it is characterised in that in step (4) reduction reaction for hydrogenation also Original, catalyst are any one in palladium carbon/hydrogen, palladium bichloride/hydrogen or Raney's nickel/hydrogen, and the pressure of hydrogenation reaction is 0.2～0.5MPa, the temperature of reaction is 25～40 DEG C.
7. a kind of midbody compound IV for preparing Ta Simeiqiong, is characterised by that structural formula is as follows：
8. profit requires the synthetic method of the midbody compound IV described in 7, it is characterised in that by described in claim 1 Midbody compound II add sodium metaperiodate catalyst in tetrahydrofuran solvent, 0～5 DEG C carry out aoxidizing it is anti- Should, obtain intermediate compound III；Then sodium borohydride effect under 0～15 DEG C carry out reduction reaction, obtain Compound IV crude products, recrystallize in ethyl acetate and petroleum ether mixed solvent.
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