CN108047092A - A kind of synthetic method of LCZ696 intermediates - Google Patents
A kind of synthetic method of LCZ696 intermediates Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
- C07C29/103—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers
- C07C29/106—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers of oxiranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
Abstract
The invention discloses a kind of synthetic methods of LCZ696 intermediates.4 bromo biphenyls, magnesium, organic solvent, iodine are triggered, then acidolysis, reaction, isolated LCZ696 intermediates.The present invention is artificial chemical synthesis LCZ696 intermediates, and a kind of cheap industrialized producing technology is provided for LCZ696 intermediates；Process route is easy to operate, and reaction condition is mild, and safety, environmental protection, raw material is cheap and easy to get, and industrial Applicability is strong, and the product yield and purity of preparation are high, and impurity is few.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of synthetic method of LCZ696 intermediates.
Background technology
LCZ696 is more effective in terms of cardiovascular death, heart failure admission rate and All-cause death is reduced, and tolerance is more preferable, tool
There are unique a variety of neuroendocrine effects, there is Mutiple Targets neuroendocrine blocking effect, it is fine for heart failure effect.
(R)-tertiary butyl (- 3 hydroxy propane -2- bases of 1- ([1,1 '-biphenyl] -4- bases)) carbamate is as in LCZ696
Mesosome has a vast market prospect.But current technology is a large amount of, solvent cost is high, and cumbersome, process cycle is long, and sets
The deficiencies of standby loss is greatly and yield is relatively low, therefore explore new (R)-tertiary butyl (1- ([1,1 '-biphenyl] -4- bases) -3 hydroxyls third
Alkane -2- bases) carbamate technique, reducing production cost has become emphasis of the recent LCZ696 in relation to research.
The content of the invention
The object of the present invention is to provide a kind of more economical, yield higher and easy to operate, safe and environment-friendly, reaction conditions
Mildly, the synthetic method of the strong LCZ696 intermediates of industrial Applicability.
The present invention is achieved by the following technical solution：
A kind of synthetic method of LCZ696 intermediates includes step：
S1. 4- bromo biphenyls, magnesium, organic solvent are added in reactor, adds at 40-45 DEG C of iodine grain and trigger, be added dropwise
4- bromo biphenyl organic solutions are cooled to 0-5 DEG C after reacting 1-2h, add in cuprous iodide, continue to be cooled to-15-- 20 DEG C, be added dropwise
(S)-epoxychloropropane of organic solvent dissolving, is stirred to react 2.0h；
S2. acid solution is instilled into reaction kettle, after being added dropwise, 30.0-40.0 DEG C is heated to, is sufficiently stirred 0.5-
2.0h, stratification collect tetrahydrofuran phase, steam solid, and water is mutually extracted with dissolution solvent, merge organic phase and dissolve solid
Heat filtering is carried out after body, is evaporated under reduced pressure organic phase；
S3. absolute ethyl alcohol is added in into reaction kettle, is uniformly mixed, is warming up to 50.0-60.0 DEG C, stops heating, to reaction
Level-one water is added dropwise in kettle, 1.0-1.5h is finished, and mother liquor is cooled to 10.0-25.0 DEG C, insulated and stirred 1.0h；Filtering, filter cake are used
One-stage water wash washs to obtain wet crude product, and wet crude product at 40.0-45.0 DEG C of hexamethylene with being beaten, then is cooled to 5.0-10.0 DEG C, filters, makes
Dry product is washed with hexamethylene；
S4. step S3 products therefroms, toluene, triphenylphosphine, succimide are entered in reactor to stir, azo two is added dropwise
The mixed liquor of formic acid diisopropyl ester and toluene, is added dropwise rear 0-5.0 DEG C of heat preservation 2h, and revolving removes toluene, adds in hydrochloric acid and water
Reaction 15-20h is hydrolyzed at a temperature of 100-108 DEG C, heating liquid separation after having hydrolyzed, organic phase, which is put into, to be added in the kettle of toluene
Stirring, is down to 15.0-25.0 DEG C, insulated and stirred 1.0h, and filtering obtains crude material, upper strata aqueous phase cooling after being washed with toluene
It to 15.0-25.0 DEG C of stirring 1.0h, then filters and also obtains crude material, crude material is beaten after merging with dichloromethane, is dropped
Temperature stirs 1.0h to 10.0-35.0 DEG C, and filtering is washed with dichloromethane, is dried to obtain fine work product；
S5. 95% ethyl alcohol is added in a kettle, fine work product, triethylamine made from step S4, be warming up to 50.0-60.0
DEG C, return stirring dissolving 1.0h；Addition activated carbon decolorizing, heat filtering, one-stage water wash has been dissolved to wash；Then it is water-soluble that potassium carbonate is added dropwise
Liquid stirs 30.0min to reaction solution pH to 8.0-9.0, keeps the temperature 50.0-55.0 DEG C；Be slowly added dropwise di-tert-butyl dicarbonic acid ester with
95% ethanol water is into reaction kettle, and drop finishes, 50.0-55.0 DEG C of insulated and stirred 1.0h；Then level-one water is added dropwise, drips
Finish, be down to 25.0-30.0 DEG C of stirring 1.0h；Then filter, filter cake is 6.0-7.0 with level-one water wash to pH, filters wet thick
Product product；Wet crude material is down to 25.0-30.0 DEG C of stirring 1.0h, the stirring of level-one water with 1.0h is beaten at 50-65 DEG C of petroleum ether
Layering, is washed till water mutually to be colourless, and filtering with petroleum ether, is dried to obtain intermediate sterling.
The synthetic route of the present invention is as follows：
Grignard Reagent dosage and cuprous iodide dosage are allocated in right amount, avoid and filter plant is blocked in production process, are shortened
Filtration time, reduces security risk；Directly organic layer is not filtered after layering, not only using extraction step in step S2
Energy consumption is reduced, also improves the quality of product.
Further, in the synthetic method of above-mentioned LCZ696 intermediates, the organic solvent be tetrahydrofuran, the dissolving
Solvent is tetrahydrofuran.
Further, in the synthetic method of above-mentioned LCZ696 intermediates, magnesium, 4- bromo biphenyls, iodine in the step S1
Grain, cuprous iodide, the quality amount ratio of (S)-epoxychloropropane are (25-30)：(240-250)：(0.1-0.2)：(1.5-
2.5)：(100-110).
It is further preferred, in the synthetic method of above-mentioned LCZ696 intermediates, magnesium in the step S1,4- bromo biphenyls,
Iodine grain, cuprous iodide, the quality amount ratio of (S)-epoxychloropropane are 27.38：250：0.125：2：109.
Further, in the synthetic method of above-mentioned LCZ696 intermediates, the acid solution in the step S2 is hydrochloric acid solution.
Further, in the synthetic method of above-mentioned LCZ696 intermediates, washed product obtained by step S3 in the step S4,
Triphenylphosphine, succimide, the quality amount ratio of diisopropyl azodiformate are (55-65)：(70-75)：(25-30)：
(55-60)。
It is further preferred that in the synthetic method of above-mentioned LCZ696 intermediates, washing obtained by step S3 in the step S4
Product, triphenylphosphine, succimide, the quality amount ratio of diisopropyl azodiformate are 60：73.4：26.4：59.
The present invention is artificial chemical synthesis LCZ696 intermediates, and a kind of cheap industrialization is provided for LCZ696 intermediates
Production technology；Process route is easy to operate, and reaction condition is mild, and safety, environmental protection, raw material is cheap and easy to get, and industrial Applicability is strong, system
Standby product yield and purity are high, and impurity is few.
Specific embodiment
With reference to specific embodiment, the present invention will be further described.The embodiment is only being preferably implemented for the present invention
Example, is not intended to limit the invention, for those skilled in the art, the present invention can have various changes and change
Change.Within the spirit and principles of the invention, any modifications, equivalent replacements and improvements are made should be included in the present invention
Protection domain within.In each embodiment parts by weight are referred both to without signified component number in the case of specified otherwise.
Embodiment 1
1. 12.5g 4- bromo biphenyls, 27.38g magnesium, 50g tetrahydrofurans are added in reactor, 0.125g iodines are added in
Grain triggers, and adds 200g tetrahydrofurans, and 237.5g4- bromo biphenyls and 350g tetrahydrofuran mixed solutions is added dropwise, instead in 40 DEG C of temperature control
4 DEG C are cooled to after answering 2h, adds in 2g cuprous iodides, continues to be cooled to -15 DEG C, 109g (S)-epoxychloropropane and 109g tetra- is added dropwise
Hydrogen furan mixture, is stirred to react 2.0h；
2. instilling acid solution into reaction kettle, after being added dropwise, 30 DEG C are heated to, is sufficiently stirred 0.5h, stratification,
Tetrahydrofuran phase is collected, steams solid, water is mutually extracted with dissolution solvent, and hot mistake is carried out after merging organic phase and dissolved solid
Filter is evaporated under reduced pressure organic phase；
It 3. adding in absolute ethyl alcohol into reaction kettle, is uniformly mixed, is warming up to 60 DEG C, stop heating, be added dropwise into reaction kettle
Level-one water, 1h are finished, and mother liquor are cooled to 20 DEG C, insulated and stirred 1h；Filtering, filter cake washs to obtain wet crude product with one-stage water wash, wet thick
Product at 45 DEG C of hexamethylene with being beaten, then is cooled to 5 DEG C, filters, and dry product is washed using hexamethylene；
4. 60g steps 3 products therefrom, 531.8g toluene, 73.4g triphenylphosphines, 26.4g succimides are entered into reactor
The mixed liquor of 59g diisopropyl azodiformates and 59g toluene is added dropwise in middle stirring, and 0 DEG C of heat preservation 2h, revolving are removed after being added dropwise
Toluene is removed, 122g hydrochloric acid is added in and 122g water is warming up to 100 DEG C
Reaction 20h is hydrolyzed, heating liquid separation after having hydrolyzed, organic phase is put into the kettle for adding in 122g toluene and stirs, drops
To 15 DEG C, insulated and stirred 1h, filtering, filter cake obtains crude material after being washed with toluene, and upper strata aqueous phase, which cools down 15 DEG C, stirs 1h, so
After filter and also obtain crude material, crude material is beaten after merging with dichloromethane, is cooled to 20 DEG C, stirs 1h, is filtered, and is used
The washing of 40g dichloromethane is dried to obtain fine work product；
5. adding in 95% ethyl alcohol of 134g, 49.22g triethylamines in fine work product made from step 4,50 DEG C are warming up to, is returned
Flow stirring and dissolving 1h；Addition activated carbon decolorizing, heat filtering, one-stage water wash has been dissolved to wash；Then wet chemical is added dropwise to anti-
Liquid pH to 8.2 is answered, stirs 30.0min, keeps the temperature 50 DEG C；The second of 59.42g di-tert-butyl dicarbonic acid esters and 20g 95% is slowly added dropwise
The mixed solution of alcohol solution is into reaction kettle, and drop finishes, 55 DEG C of insulated and stirred 1h；Then 450g level-one water is added dropwise, is added dropwise,
It is down to 8 DEG C of stirring 1h；Then filter, filter cake level-one water wash to pH is 6.5, filters to obtain wet crude material；Wet crude material
Purify water washing with 120g, then filter cake is added in 300g petroleum ethers and 60g purified waters, is warming up at 60 DEG C and is beaten 1h, is dropped
To 25 DEG C of stirring 1h, the stirring layering of level-one water is washed till water mutually to be colourless, and with petroleum ether, it is pure to be dried to obtain intermediate for filtering
Product.Mole total recovery of intermediate sterling is that 81.74%, HPLC purity is 99.24%.
Embodiment 2
1. 10g 4- bromo biphenyls, 30g magnesium, 50g tetrahydrofurans are added in reactor, add in 0.1g iodines grain and trigger,
200g tetrahydrofurans are added, 237.5g4- bromo biphenyls and 350g tetrahydrofuran mixed solutions is added dropwise in 45 DEG C of temperature control, after reacting 1-2h
0-5 DEG C is cooled to, adds in 2g cuprous iodides, continues to be cooled to -20 DEG C, 100g (S)-epoxychloropropane and 109g tetrahydrochysene furans is added dropwise
It mutters mixture, is stirred to react 2.0h；
2. instilling acid solution into reaction kettle, after being added dropwise, 40 DEG C are heated to, is sufficiently stirred 1h, stratification is received
Collecting tetrahydrofuran phase, steam solid, water is mutually extracted with dissolution solvent, and heat filtering is carried out after merging organic phase and dissolved solid,
It is evaporated under reduced pressure organic phase；
It 3. adding in absolute ethyl alcohol into reaction kettle, is uniformly mixed, heats up 55 DEG C, stop heating, one is added dropwise into reaction kettle
Grade water, 1.5h are finished, and mother liquor are cooled to 10 DEG C, insulated and stirred 1h；Filtering, filter cake washs to obtain wet crude product with one-stage water wash, wet thick
Product at 45 DEG C of hexamethylene with being beaten, then is cooled to 10 DEG C, filters, and dry product is washed using hexamethylene；
4. 60g steps 3 products therefrom, 531.8g toluene, 75g triphenylphosphines, 28g succimides are entered in reactor to stir
It mixes, the mixed liquor of 55g diisopropyl azodiformates and 55g toluene is added dropwise, 3 DEG C of heat preservation 2h, revolving remove first after being added dropwise
Benzene, adds in 122g hydrochloric acid and 122g water is warming up to 105 DEG C and reaction 20h is hydrolyzed, and heating liquid separation, organic phase are put into after having hydrolyzed
It adding in the kettle of 122g toluene and stirs, be down to 15 DEG C, insulated and stirred 1h, filtering, filter cake obtains crude material after being washed with toluene,
Upper strata aqueous phase is cooled to 25 DEG C of stirring 1h, then filters and also obtains crude material, and crude material is beaten after merging with dichloromethane,
10 DEG C are cooled to, stirs 1h, filtering is washed with 40g dichloromethane, is dried to obtain fine work product；
5. adding in 95% ethyl alcohol of 134g, 49.22g triethylamines in fine work product made from step 4,55 DEG C are warming up to, is returned
Flow stirring and dissolving 1h；Addition activated carbon decolorizing, heat filtering, one-stage water wash has been dissolved to wash；Then wet chemical is added dropwise to anti-
Liquid pH to 8.2 is answered, stirs 30min, keeps the temperature 50 DEG C；The ethyl alcohol of 59.42g di-tert-butyl dicarbonic acid esters and 20g 95% is slowly added dropwise
The mixed solution of aqueous solution is into reaction kettle, and drop finishes, 55 DEG C of insulated and stirred 1h；Then 450g level-one water is added dropwise, is added dropwise, drops
To 10 DEG C of stirring 1h；Then filter, filter cake level-one water wash to pH is 6.8, filters to obtain wet crude material；Wet crude material is used
120g purifies water washing, and then filter cake is added in 300g petroleum ethers and 60g purified waters, is warming up at 60 DEG C and is beaten 1h, is down to
25 DEG C of stirring 1h, level-one water stirring layering, are washed till water mutually to be colourless, and with petroleum ether, it is pure to be dried to obtain intermediate for filtering
Product.Mole total recovery of intermediate sterling is that 83.33%, HPLC purity is 98.6%.
Embodiment 3
1. 10g 4- bromo biphenyls, 25g magnesium, 50g tetrahydrofurans are added in reactor, add in 0.2g iodines grain and trigger,
200g tetrahydrofurans are added, 237.5g 4- bromo biphenyls and 350g tetrahydrofuran mixed solutions is added dropwise in 45 DEG C of temperature control, after reacting 1h
5 DEG C are cooled to, adds in 1.5g cuprous iodides, continues to be cooled to -18 DEG C, 110g (S)-epoxychloropropane and 110g tetrahydrochysene furans is added dropwise
It mutters mixture, is stirred to react 2h；
2. instilling acid solution into reaction kettle, after being added dropwise, 30 DEG C are heated to, is sufficiently stirred 0.5-2.0h, stood
Layering collects tetrahydrofuran phase, steams solid, and water is mutually extracted with dissolution solvent, is carried out after merging organic phase and dissolved solid
Heat filtering is evaporated under reduced pressure organic phase；
It 3. adding in absolute ethyl alcohol into reaction kettle, is uniformly mixed, is warming up to 50 DEG C, stop heating, be added dropwise into reaction kettle
Level-one water, 1h are finished, and mother liquor are cooled to 20 DEG C, insulated and stirred 1h；Filtering, filter cake washs to obtain wet crude product with one-stage water wash, wet thick
Product at 40 DEG C of hexamethylene with being beaten, then is cooled to 6 DEG C, filters, and dry product is washed using hexamethylene；
4. 60g steps 3 products therefrom, 531.8g toluene, 70g triphenylphosphines, 30g succimides are entered in reactor to stir
It mixes, the mixed liquor of 60g diisopropyl azodiformates and 60g toluene is added dropwise, 4 DEG C of heat preservation 2h, revolving remove first after being added dropwise
Benzene, adds in 122g hydrochloric acid and 122g water is warming up to 108 DEG C and reaction 16h is hydrolyzed, and heating liquid separation, organic phase are put into after having hydrolyzed
It adds in the kettle of 122g toluene and stirs, be down to 15.0-25.0 DEG C, insulated and stirred 1h, filtering, filter cake obtains slightly after being washed with toluene
Product product, upper strata aqueous phase are cooled to 15 DEG C of stirring 1h, then filter and also obtain crude material, crude material uses dichloromethane after merging
Alkane is beaten, and is cooled to 10 DEG C, stirs 1h, and filtering is washed with 40g dichloromethane, is dried to obtain fine work product；
5. adding in 95% ethyl alcohol of 134g, 49.22g triethylamines in fine work product made from step 4,60 DEG C are warming up to, is returned
Flow stirring and dissolving 1h；Addition activated carbon decolorizing, heat filtering, one-stage water wash has been dissolved to wash；Then wet chemical is added dropwise to anti-
Liquid pH to 8.7 is answered, stirs 30min, keeps the temperature 50 DEG C；The ethyl alcohol of 59.42g di-tert-butyl dicarbonic acid esters and 20g 95% is slowly added dropwise
The mixed solution of aqueous solution is into reaction kettle, and drop finishes, 55 DEG C of insulated and stirred 1h；Then 450g level-one water is added dropwise, is added dropwise, drops
To 10 DEG C of stirring 1h；Then filter, filter cake level-one water wash to pH is 6.2, filters to obtain wet crude material；Wet crude material is used
120g purifies water washing, and then filter cake is added in 300g petroleum ethers and 60g purified waters, is warming up at 50-65 DEG C and is beaten 1h, drops
To 30 DEG C of stirring 1h, the stirring layering of level-one water is washed till water mutually to be colourless, and with petroleum ether, it is pure to be dried to obtain intermediate for filtering
Product.Mole total recovery of intermediate sterling is that 75%, HPLC purity is 99.6%.
Claims (7)
1. a kind of synthetic method of LCZ696 intermediates, which is characterized in that including step：
S1. 4- bromo biphenyls, magnesium, organic solvent are added in reactor, adds at 40-45 DEG C of iodine grain and trigger, 4- bromines are added dropwise
Biphenyl organic solution is cooled to 0-5 DEG C after reacting 1-2h, adds in cuprous iodide, continues to be cooled to-15-- 20 DEG C, be added dropwise organic
(S)-epoxychloropropane of solvent dissolving, is stirred to react 2.0h；
S2. acid solution is instilled into reaction kettle, after being added dropwise, 30.0-40.0 DEG C is heated to, is sufficiently stirred 0.5-2.0h,
Stratification collects tetrahydrofuran phase, steams solid, and water is mutually extracted with dissolution solvent, after merging organic phase and dissolved solid
Heat filtering is carried out, is evaporated under reduced pressure organic phase；
S3. absolute ethyl alcohol is added in into reaction kettle, is uniformly mixed, is warming up to 50.0-60.0 DEG C, stops heating, into reaction kettle
Level-one water is added dropwise, 1.0-1.5h is finished, and mother liquor is cooled to 10.0-25.0 DEG C, insulated and stirred 1.0h；Filtering, filter cake level-one
Water washing obtains wet crude product, and wet crude product at 40.0-45.0 DEG C of hexamethylene with being beaten, then is cooled to 5.0-10.0 DEG C, filters, uses ring
Dry the product of hexane washing；
S4. step S3 products therefroms, toluene, triphenylphosphine, succimide are entered in reactor to stir, azoformic acid is added dropwise
Rear 0-5.0 DEG C of heat preservation 2h is added dropwise in the mixed liquor of diisopropyl ester and toluene, and revolving removes toluene, adds in hydrochloric acid and water exists
Reaction 15-20h is hydrolyzed at a temperature of 100-108 DEG C, heating liquid separation after having hydrolyzed, organic phase is put into the kettle for adding in toluene and stirs
It mixes, is down to 15.0-25.0 DEG C, insulated and stirred 1.0h, filtering obtains crude material, upper strata aqueous phase is cooled to after being washed with toluene
15.0-25.0 DEG C of stirring 1.0h, then filters and also obtains crude material, and crude material is beaten after merging with dichloromethane, is cooled down
To 10.0-35.0 DEG C, 1.0h is stirred, filtering is washed with dichloromethane, is dried to obtain fine work product；
S5. 95% ethyl alcohol is added in a kettle, fine work product, triethylamine made from step S4, be warming up to 50.0-60.0 DEG C,
Return stirring dissolves 1.0h；Addition activated carbon decolorizing, heat filtering, one-stage water wash has been dissolved to wash；Then wet chemical is added dropwise
To reaction solution pH to 8.0-9.0,30.0min is stirred, keeps the temperature 50.0-55.0 DEG C；Be slowly added dropwise di-tert-butyl dicarbonic acid ester with
95% ethanol water is into reaction kettle, and drop finishes, 50.0-55.0 DEG C of insulated and stirred 1.0h；Then level-one water is added dropwise, drips
Finish, be down to 25.0-30.0 DEG C of stirring 1.0h；Then filter, filter cake is 6.0-7.0 with level-one water wash to pH, filters wet thick
Product product；Wet crude material is down to 25.0-30.0 DEG C of stirring 1.0h, the stirring of level-one water with 1.0h is beaten at 50-65 DEG C of petroleum ether
Layering, is washed till water mutually to be colourless, and filtering with petroleum ether, is dried to obtain intermediate sterling.
2. the synthetic method of LCZ696 intermediates according to claim 1, which is characterized in that
The organic solvent is tetrahydrofuran, and the dissolution solvent is tetrahydrofuran.
3. the synthetic method of LCZ696 intermediates according to claim 1, which is characterized in that
Magnesium, 4- bromo biphenyls, iodine grain, cuprous iodide, the quality amount ratio of (S)-epoxychloropropane are in the step S1
(25-30)：(240-250)：(0.1-0.2)：(1.5-2.5)：(100-110).
4. the synthetic method of LCZ696 intermediates according to claim 1, which is characterized in that
Magnesium, 4- bromo biphenyls, iodine grain, cuprous iodide, the quality amount ratio of (S)-epoxychloropropane are in the step S1
27.38：250：0.125：2：109.
5. the synthetic method of LCZ696 intermediates according to claim 1, which is characterized in that
Acid solution in the step S2 is hydrochloric acid solution.
6. the synthetic method of LCZ696 intermediates according to claim 1, which is characterized in that
Washed product, triphenylphosphine, succimide, the matter of diisopropyl azodiformate obtained by step S3 in the step S4
It is (55-65) to measure amount ratio：(70-75)：(25-30)：(55-60).
7. the synthetic method of LCZ696 intermediates according to claim 1, which is characterized in that
Washed product, triphenylphosphine, succimide, the matter of diisopropyl azodiformate obtained by step S3 in the step S4
It is 60 to measure amount ratio：73.4：26.4：59.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503404A (en) * | 2018-12-28 | 2019-03-22 | 凯瑞斯德生化(苏州)有限公司 | A kind of preparation method of LCZ-696 key intermediate |
| CN110133149A (en) * | 2019-05-31 | 2019-08-16 | 重庆三圣实业股份有限公司 | A kind of method of separation determination LCZ696 and its impurity |
| WO2023206874A1 (en) * | 2022-04-29 | 2023-11-02 | 凯特立斯（深圳）科技有限公司 | Sacubitril intermediate, preparation method therefor, and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109503404A (en) * | 2018-12-28 | 2019-03-22 | 凯瑞斯德生化(苏州)有限公司 | A kind of preparation method of LCZ-696 key intermediate |
| CN110133149A (en) * | 2019-05-31 | 2019-08-16 | 重庆三圣实业股份有限公司 | A kind of method of separation determination LCZ696 and its impurity |
| CN110133149B (en) * | 2019-05-31 | 2022-05-24 | 重庆三圣实业股份有限公司 | Method for separating and measuring LCZ696 and impurities thereof |
| WO2023206874A1 (en) * | 2022-04-29 | 2023-11-02 | 凯特立斯（深圳）科技有限公司 | Sacubitril intermediate, preparation method therefor, and use thereof |
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