CN106316889A - Preparation method of Edoxaban intermediate - Google Patents
Preparation method of Edoxaban intermediate Download PDFInfo
- Publication number
- CN106316889A CN106316889A CN201510330875.2A CN201510330875A CN106316889A CN 106316889 A CN106316889 A CN 106316889A CN 201510330875 A CN201510330875 A CN 201510330875A CN 106316889 A CN106316889 A CN 106316889A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- uniform temperature
- ether
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an Edoxaban intermediate. The preparation method comprises a, preparing a compound 2 from a compound 1 as a raw material, b, producing a novel compound (1S, 3S, 6R)-7-oxabicyclo[4. 1. 0]heptane-3-carboxylic acid as a compound 3c from the compound 2 under conditions of a certain temperature, an alkali and a solvent, c, producing a novel compound (1S, 3S, 4R)-3-amino-4-hydroxycyclohexanecarboxylic acid as a compound 4c from the compound 3c under conditions of a certain temperature, ammonium hydroxide and a solvent, and d, producing a compound 5c from the compound 4c under conditions of a certain temperature, an alkali, a solvent and di-tert-butyl dicarbonate (Boc2O). Compared with the prior art, the preparation method has the advantages of high yield, good product quality, simple operation, purification easiness, good process operationality and large scale production easiness.
Description
Technical field
The present invention relates to the preparation method of a kind of compound, be specifically related to one and prepare Stuart factor (FXa) blocker Yi Dusha
The improvement chemical method of the intermediate of class, relates more specifically to a kind of high yield, high-purity, it is easy to the preparation Yi Dushaban of control
The chemical method of intermediate.
Background technology
The Yi Dushaban of company altogether of Japan the one or three has been approved to list in Japan, at the brand name of Japan on April 22nd, 2011
For Lixiana.Yi Dushaban 15mg and 30mg oral tablet are used for preventing Orthopaedics Major Operation posterior vein thromboembolism (VTE).
Clinical studies show, Yi Dushaban can reversibly factor Xa anticoagulant, to total knee arthroplasty, total hip replacement
Art and hip fracture patient with operation have good treatment benefit, and effectiveness is better than the most commonly used Enoxaparin.
In January, 2015, Yi Dushaban (Edoxaban) obtains FDA approval and lists in the U.S., the entitled Savaysa of brand,
For 60mg oral tablet once-a-day.It is applicable to reduce apoplexy and the general bolt of Nonvalvular atrial fibrillation (NVAF) patient
The risk of plug (SE).It is in III phase clinical development in other regions such as Europe.Supervision department is the most examining Yi Dushabanzhi
Treat the application of venous thromboembolism (VTE).
The intermediate of Yi Dushaban, structure is as follows:
The method of preparation intermediate E dox-C mainly has two kinds at present:
Method one [WO2003000657, WO2003000680]:
As shown in the synthetic method one of following Edox-C, this route with (1S)-3-cyclohexene-1-carboxylic acid (compound 1) as raw material,
Obtaining Edox-C through 12 step reactions, total recovery is 10.0%.This route is longer, has multistep reaction to need column chromatography for separation pure
Changing, this route compound 3a is during ammonolysis prepares compound 4a, and in compound 3a, ester group is easily by ammonolysis, and reaction is very
Difficult control.
The synthetic method one of Edox-C
Method two [CN200680033991, WO2014081047]:
As shown in the synthetic method two of following Edox-C, this route with (1S)-3-cyclohexene-1-carboxylic acid (compound 1) as raw material,
Obtaining Edox-C through 8 step reactions, total recovery is 30.1%.The condition of this route reaction is gentleer, and whole piece route does not has
Column chromatographic isolation and purification step, but find when preparing compound 4b according to the condition of patent, and compound 2b is in diformazan aqueous amine
After ammonolysis obtains compound 3b in solution, it is impossible to self cyclization, obtain compound 4b, even if adding highly basic also have the chemical combination of 50%
Thing 3b can not convert, and the diformamide group of compound 3b has a big chunk to be hydrolyzed.
The synthetic method two of Edox-C
Therefore, in the urgent need to a kind of economy, safely, be prone to technique produce amplify feasible Yi Dushaban intermediate synthesis technique
Method.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of a kind of Yi Dushaban intermediate, its compared with the conventional method,
Yield is higher, and quality is more preferable, and easy and simple to handle, it is easy to purification, the process operability of the method is strong, it is easy to amplifies and produces.
The invention provides a new important intermediate of synthesis Edox-C, i.e. compound 5c.
The structure of compound 5c is as follows:
Compared with the route of other synthesis Edox-C, the route yield being prepared Edox-c by compound 5c is high, it is easy to purification.
The present invention provides the preparation method of a kind of Yi Dushaban midbody compound 5c, and its step includes:
(a) referenced patent WO2003000657, WO2003000680 method, prepare (1S, 4S, 5S)-4-with compound 1 for raw material
Iodo-6-oxabicyclo [3.2.1]-octane-7-ketone, i.e. compound 2.
B () compound 2, at uniform temperature, alkali, under solvent condition, generates noval chemical compound (1S, 3S, 6R)-7-oxabicyclo [4.1.0]
Heptane-3-carboxylic acid, i.e. compound 3c.
C () compound 3c generates noval chemical compound (1S, 3R, 4R)-3-amino-4-hydroxy under uniform temperature, solvent and aqueous ammonia conditions
Cyclohexane-carboxylic acid, i.e. compound 4c.
D () compound 4c is at uniform temperature, alkali, solvent and Bis(tert-butoxycarbonyl)oxide (Boc2O) compound 5c is generated under the conditions of.
(e) compound 5c under uniform temperature, alkali, condensing agent and solvent condition, generate the compound tert-butyl group (1R, 2R,
5S)-5-[(dimethylamino) hydroxyl]-2-hydroxy-cyclohexyl carbonyl } carbaminate, i.e. formula compound 6b.
F () referenced patent CN200680033991, WO2014081047 method is prepared through compound 7b and 8b by compound 6b
Obtain Edox-C.
Process is as follows:
Wherein,
In step (b), described uniform temperature is 0-100 DEG C, preferably 20 to 30 DEG C.
In step (b), described alkali is sodium hydroxide, potassium hydroxide, Lithium hydrate, one or more in potassium carbonate etc..
In step (b), any one or a few of following solvent chosen by described solvent: ether, methyl tertiary butyl ether(MTBE), oxolane,
Acetone, acetonitrile, dioxane, water etc..
In step (c), described uniform temperature is 0-100 DEG C, preferably 30 to 50 DEG C.
In step (c), any one or a few of following solvent chosen by described solvent: methanol, ethanol, isopropanol, the tert-butyl alcohol,
Ether, methyl tertiary butyl ether(MTBE), oxolane, acetone, acetonitrile, dioxane, water etc..
In step (d), described uniform temperature is-20-100 DEG C, preferably 20 to 30 DEG C.
In step (d), described alkali includes organic base and inorganic base, organic base be selected from triethylamine, diisopropyl ethyl amine, pyridine,
N, N-lutidines, one or more in N-methylmorpholine etc., inorganic base is selected from sodium hydroxide, potassium hydroxide, hydroxide
Lithium, potassium carbonate, sodium bicarbonate, one or more in sodium carbonate etc..
In step (d), any one or a few of following solvent chosen by described solvent: methanol, ethanol, isopropanol, the tert-butyl alcohol,
Ether, methyl tertiary butyl ether(MTBE), oxolane, acetone, acetonitrile, water.
In step (e), described uniform temperature is 0-100 DEG C, preferably 20 to 30 DEG C；
In step (e), described alkali includes triethylamine, diisopropyl ethyl amine, pyridine, N, N-lutidines, N-methyl
One or more in quinoline etc.；
In step (e), described condensing agent includes carbonyl dimidazoles (CDI), 1-ethyl-(3-dimethylaminopropyl) carbodiimide salt
One or more in hydrochlorate (EDC.HCl) and 1-hydroxy benzo triazole (HOBT) etc.；
In step (e), any one or a few of following solvent chosen by described solvent: halogenated hydrocarbon such as dichloromethane, chloroform, and four
Chlorination carbon, 1,2-dichloroethanes etc.；Mystery class such as oxolane, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), methyltetrahydrofuran,
Dioxane, glycol dimethyl ether etc.；Arene such as toluene, chlorobenzene, dimethylbenzene etc.；Alkanes such as petroleum ether, normal heptane,
Normal hexane, hexamethylene etc.；Esters such as ethyl acetate, methyl acetate, isopropyl acetate etc..
Compared with prior art, the beneficial effects of the present invention is: the inventive method (1S)-3-cyclohexene-l-carboxylic acid, pass through
Eight step reactions obtain Edox-C, and total recovery is 41.5%, and more existing method one (10.0%) and method two (30.1%) are
Improve (seeing method one and method two in background technology).The present invention overcomes compound 3a in method one to prepare in ammonolysis
During compound 4a, ethyl ester, the most easily by ammonolysis, reacts shortcoming the most rambunctious.Also overcome compound in method two
After 2b ammonolysis in dimethylamine agueous solution obtains compound 3b, it is impossible to self cyclization, obtain compound 4b, even if adding highly basic
Also the compound 3b having 50% can not convert completely, and the diformamide base of compound 3b has be hydrolyzed greatly to lack
Point.It is substantially better than existing method in the process of the present invention.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments be merely to illustrate the present invention and not
For limiting the scope of the present invention.
In all embodiments, thermometer does not corrects；1H-NMR Varian Mercury 400 nuclear magnetic resonance analyser record, chemical potential
Move and represent with δ (ppm)；Mass spectrum Agilent 6120LC-MS LC-MS instrument measures, and content HPLC external standard method is surveyed
Fixed.
Reference example 1: the synthesis of compound 2
Compound 1 (160.0g, 1.27mol) is dissolved in dichloromethane (750ml) and water (750ml), adds potassium iodide
(231.7g, 1.40mol), and ice bath cools to 0 DEG C, adds sodium bicarbonate (117.1g, 1.40mol) in batches, (emits a large amount of
Bubble, so the added-time is it is noted that control speed, heating up is not clearly).Treat that sodium bicarbonate adds, after bubble collapse, add iodine
(353.9g, 1.40mol), iodine adds complete.React 0.5 hour under ice bath, then allow system naturally be warmed up to room temperature reaction 3 little
Time.TLC plate is monitored, and reaction completely, adds sodium thiosulfate and makes system color be become colourless by atropurpureus.Stirring, stratification,
Aqueous phase is with dichloromethane back extraction once.Combined dichloromethane phase, concentrating under reduced pressure, obtaining product (314g, 98.4%) is off-white color
Solid, i.e. compound 2.
Embodiment 1: the synthesis of compound 4c
Compound 2 (160.0g, 634.8mmol) is dissolved in oxolane (400ml) and water (100ml), adds hydrogen-oxygen
Change sodium (50.0g, 1269.6mmol), be stirred vigorously, make two-phase mixtures uniform.45 DEG C are reacted 2 hours, and TLC plate is monitored, instead
Should be complete, obtain compound 3c.In reactant liquor, add ammonia (150ml), and make system temperature rise to 45 DEG C of reactions 24 hours.
Reactant liquor is concentrated, removes oxolane and ammonia under reduced pressure, obtain grease (250g), i.e. compound 4c.
Embodiment 2: the synthesis of compound 4c
Compound 2 (16.0g, 63.5mmol) is dissolved in dioxane (40ml) and water (10ml), adds sodium hydroxide
(5.1g, 127.0mmol), is stirred vigorously, and makes two-phase mixtures uniform.45 DEG C are reacted 2 hours, and TLC plate is monitored, and reaction is complete,
Obtain compound 3c.In reactant liquor, add ammonia (15ml), and be warming up to 45 DEG C of reactions 20 hours.Reactant liquor is concentrated, subtracts
Pressure is evaporated off dioxane and ammonia, obtains grease (24.0g), i.e. compound 4c.
Embodiment 3: the synthesis of compound 4c
Compound 2 (16.0g, 63.5mmol) is dissolved in acetone (40ml) and water (10ml), addition potassium hydroxide (7.1g,
127.0mmol), it is stirred vigorously, makes two-phase mixtures uniform.20 DEG C are reacted 2 hours, and TLC plate is monitored, and reaction is complete, obtaining
Compound 3c.In reactant liquor, add ammonia (15ml), and be warming up to 50 DEG C of reactions 20 hours.Being concentrated by reactant liquor, decompression is steamed
Except acetone and ammonia, obtain grease (24.6g), i.e. compound 4c.
Embodiment 4: the synthesis of compound 4c
Compound 2 (16.0g, 63.5mmol) is dissolved in ether (40ml) and water (10ml), adds Lithium hydrate. one
Water (5.3g, 127.0mmol), is stirred vigorously, and makes two-phase mixtures uniform.30 DEG C are reacted 2 hours, and TLC plate is monitored, and has reacted
Entirely, compound 3c is obtained.In reactant liquor, add ammonia (15ml), and be warming up to 30 DEG C of reactions 24 hours.Reactant liquor is concentrated,
Remove ether and ammonia under reduced pressure, obtain grease (24.0g), i.e. compound 4c.
Embodiment 5: the synthesis of compound 4c
Compound 2 (16.0g, 63.5mmol) is dissolved in methyl tertiary butyl ether(MTBE) (40ml) and water (10ml), adds carbonic acid
Potassium (17.6g, 127.0mmol), is stirred vigorously.0 DEG C is reacted 2 hours, and TLC plate is monitored, and reaction completely, obtains compound 3c.
Adding ammonia (15ml) in reactant liquor, ice bath is cooled to 0 DEG C of reaction 24h.Reactant liquor is concentrated, removes methyl-tert fourth under reduced pressure
Base ether and ammonia, obtain grease (24.5g), i.e. compound 4c.
Embodiment 6: the synthesis of compound 4c
Compound 2 (16.0g, 63.5mmol) is dissolved in acetonitrile (40ml) and water (10ml), adds Lithium hydrate. one
Water (5.3g, 127.0mmol), is stirred vigorously, and makes two-phase mixtures uniform.30 DEG C are reacted 2 hours, and TLC plate is monitored, and has reacted
Entirely, compound 3c is obtained.In reactant liquor, add ammonia (15ml), and make system temperature rise to 30 DEG C of reaction 24h.Will reaction
Liquid concentrates, and steams acetonitrile and ammonia, obtains grease (24.8g), i.e. compound 4c.
Embodiment 7: the synthesis of compound 5c
Methanol (800ml), triethylamine (64.1g, 634.8mmoL), stirring and dissolving, ice is added in compound 4c (250g)
Bath cools to 0 DEG C, adds (Boc) in batches2O (166.0g, 761.8mmol), reacts 30 minutes, and LC-MS monitors,
Completely, decompression steams methanol in reaction, dissolves with ethyl acetate (600ml)/water (200ml), and ice bath cools to 0-10 DEG C,
Add dilute hydrochloric acid regulation pH value to about 6.Aqueous phase ethyl acetate (300ml × 2) is washed, combined ethyl acetate phase, anhydrous slufuric acid
Sodium is dried, and is concentrated to give yellow oil (159.5g), i.e. compound 5c.
Compound 5c:1H-NMR(400MHz,CDCl3)δ6.81(s,1H),4.71(s,1H),4.29(s,1H),
2.93 (s, 1H), 2.22 (t, J=10.8Hz, 3H), 1.93 (s, 1H), 1.84 (s, 1H), 1.69 (s, 1H),
1.49(s,9H).
MS:[M+H] 260.0
Embodiment 8: the synthesis of compound 5c
In compound 4c (25g), add ethanol (80ml) dissolve, be subsequently adding sodium bicarbonate (5.3g, 63.5mmoL),
Ice bath cools to-20 DEG C, adds (Boc) in batches2O (16.6g, 76.2mmol), reacts 30 minutes, and LC-MS monitors, instead
Should be complete, steam ethanol, dissolve with ethyl acetate (60ml), water (20ml), ice bath cools to 0-10 DEG C, adds dilute salt
Acid for adjusting pH value is to about 6.Aqueous phase ethyl acetate (30ml × 2) is washed.Combined ethyl acetate phase, anhydrous sodium sulfate is dried,
It is concentrated to give yellow oil (15.8g), i.e. compound 5c.
Embodiment 9: the synthesis of compound 5c
In compound 4c (25g), add oxolane (80ml) dissolve, be subsequently adding sodium hydroxide (2.5g, 63.4mmoL),
Add (Boc) in batches2O (16.6g, 76.2mmmol), back flow reaction 30 minutes, LC-MS monitors, and reaction completely, uses second
Acetoacetic ester (60ml), water (20ml) dissolve, and ice bath cools to 0-10 DEG C, add dilute hydrochloric acid regulation pH value to about 6.Water
Washing by ethyl acetate (30ml × 2) mutually, combined ethyl acetate phase, anhydrous sodium sulfate is dried, and is concentrated to give yellow oil (15.6g),
I.e. compound 5c.
Embodiment 10: the synthesis of compound 5c
In compound 4c (25g), add acetone (80ml) dissolve, be subsequently adding sodium carbonate (6.7g, 63.5mmoL), point
Batch adds (Boc)2O (16.6g, 76.1mmmol), 20 DEG C are reacted 30 minutes, and LC-MS monitors, and reaction completely, spins off third
Ketone, dissolves with ethyl acetate (60ml)/(20ml), and ice bath cools to 0-10 DEG C, adds dilute hydrochloric acid regulation pH value left to 6
The right side, aqueous phase ethyl acetate (30ml × 2) back extraction, combined ethyl acetate phase, anhydrous sodium sulfate is dried, is concentrated to give yellow oil
(15.5g), i.e. compound 5c.
Embodiment 11: the synthesis of compound 5c
In compound 4c (25g), add ether (80ml) dissolve, be subsequently adding potassium carbonate (8.8g, 63.5mmoL), point
Batch adds (Boc)2O (16.6g, 76.1mmmol), 30 DEG C are reacted 30 minutes, and LC-MS monitors, and reaction completely, uses acetic acid
Ethyl ester (60ml) dissolves with water (20ml), and ice bath cools to 0 DEG C, and-dilute hydrochloric acid regulation pH value is to about 6.Aqueous phase second
Acetoacetic ester (30ml × 2) extracts.Merge organic facies.Anhydrous sodium sulfate is dried, and is concentrated to give yellow oil (15.0g), i.e. chemical combination
Thing 5c.
Embodiment 12: the synthesis of compound 5c
In compound 4c (25g), add acetonitrile (80ml) dissolve, be subsequently adding pyridine (4.4g, 63.5mmoL), in batches
Secondary addition (Boc)2O (16.6g, 76.1mmol), 80 DEG C are reacted 30 minutes, and LC-MS monitors, and reaction completely, spins off acetonitrile,
Dissolving with water (20ml) by ethyl acetate (60ml), ice bath cools to 0-10 DEG C, adds dilute hydrochloric acid regulation pH value left to 6
The right side, aqueous phase ethyl acetate (30ml × 2) is washed, and merges organic facies.Anhydrous sodium sulfate is dried, is concentrated to give yellow oil (15.4g),
I.e. compound 5c.
Embodiment 13: the synthesis of compound 6b
Compound 5c (168.4g, 634.8mmol) is dissolved in dichloromethane (800ml), addition N-methylmorpholine (288.9g,
2856.6mmol), dimethylamine hydrochloride (124.2g, 1523.5mmol), EDC.HCl (182.5g, 952.2mmol),
HOBT (128.7g, 952.2mmol), stirring, react 3 hours at 0 DEG C, LC-MS monitors, and reaction completely, adds water (800ml)
Stirring, stands separatory, and dichloromethane is washed mutually, and saturated nacl aqueous solution is washed.Anhydrous sodium sulfate is dried 24h, is concentrated to give yellowish
Color grease (177.8g, 97.8%), i.e. compound 6b.
Embodiment 14: the synthesis of compound 6b
Compound 5c (168.4g, 634.8mmol) is dissolved in ethyl acetate (800ml), addition N-methylmorpholine (288.9g,
2856.6mmol), dimethylamine hydrochloride (124.2g, 1523.5mmol), EDC.HCl (128.5g, 952.2mmol),
HOBT (128.7g, 952.2mmol), then reacts 3 hours at 40 DEG C, and LC-MS monitors, and reaction completely, adds water (800ml)
Stirring, stands separatory, and ethyl acetate is washed mutually, and saturated nacl aqueous solution is washed.Anhydrous sodium sulfate is dried 24h, is concentrated to give yellowish
Color grease (170g), i.e. compound 6b.
Embodiment 15: the synthesis of compound 6b
Compound 5c (168.4g, 634.8mmol) is dissolved in ether (800ml), adds N, N-lutidines (288.9g),
Dimethylamine hydrochloride (124.2g), carbonyl dimidazoles (154.4g) then reacts 3 hours at 20 DEG C, and LC-MS monitors, reaction
Completely, adding water (800ml) stirring, stand separatory, ether washes with water mutually, and saturated nacl aqueous solution is washed.Anhydrous sodium sulfate is done
Dry 24h, is concentrated to give pale yellow oil (175g), i.e. compound 6b.
Embodiment 16: the synthesis of compound 6b
Compound 5c (168.4g, 634.8mmol) is dissolved in toluene (800ml), adds triethylamine (288.9g), diformazan
Amine hydrochlorate (124.2g), carbonyl dimidazoles (154.4g), stirring, react 3 hours at 100 DEG C, LC-MS monitors, reaction
Completely, adding water (800ml) stirring, stand separatory, toluene is washed mutually, and saturated nacl aqueous solution is washed.Anhydrous sodium sulfate is dried
Overnight, it is concentrated to give pale yellow oil (168g), i.e. compound 6b.
Embodiment 17: the synthesis of compound 6b
Compound 5c (168.4g, 634.8mmol) is dissolved in oxolane (800ml), addition pyridine (110.0g), and two
Methylamine hydrochloride (124.2g), carbonyl dimidazoles (154.4g) then reacts 3 hours at 30 DEG C, and LCMS monitors, reaction completely,
Adding water (800ml) stirring, stand separatory, oxolane washes with water once mutually, and saturated sodium-chloride water solution is washed once.Anhydrous
Sodium sulfate is dried overnight, and is concentrated to give pale yellow oil (170g), i.e. compound 6b.
Embodiment 18: the synthesis of compound 6b
Compound 5c (168.4g, 634.8mmol) is dissolved in normal heptane (800ml), adds diisopropyl ethyl amine (288.9g),
Dimethylamine hydrochloride (124.2g), carbonyl dimidazoles (154.4g) then reacts 3 hours at 30 DEG C, and LC-MS monitors, and has reacted
Entirely, adding water (800ml) stirring, stand separatory, normal heptane washes with water mutually, and saturated nacl aqueous solution is washed.Anhydrous sodium sulfate is done
Dry overnight, be concentrated to give pale yellow oil (165g), i.e. compound 6b.
Reference example 19: the synthesis of compound 7b
Compound 6b (177.8g, 0.62mol) is dissolved in ethyl acetate (800ml), adds triethylamine (125.2g, 1.24mol),
Ice bath cools to 0 DEG C, dropping MsCl (72ml, 0.93mol), drips complete.Remove ice bath, after reacting 3 hours under room temperature
LCMS monitors, and reaction completely, adds water (1L) in reactant liquor, stirs separatory, and aqueous phase is anti-by ethyl acetate (250ml × 2)
Extraction.Combined ethyl acetate phase, is concentrated to give yellow solid.Reflux by normal heptane (60ml) and ethyl acetate (30ml) and pull an oar
1 hour, ice bath cooled to 0-10 DEG C, filtered to obtain white solid (192.0g, 85.0%), i.e. compound 7b.
The synthesis of reference example 20:Edox-C
Hydrazoic acid,sodium salt (8.17g, 125.5mmol) and cetylpyridinium chloride (8.95g, 31.6mmol) are dissolved in water (23ml)
In, stir 1 hour, then under 60 DEG C of decompressions, remove water with toluene (200ml).Along with the removing of water, there is the solid of yellow
Separate out.When not having water to be distilled out of in system, add compound 7b (23g, 63.1mmol) and be warming up to 65 DEG C of reactions 48 hours,
LCMS monitoring reaction completely, obtains compound 8b.Add water (100ml), ethyl acetate (100ml), stir separatory, organic facies
After washing with saturated nacl aqueous solution (100ml).Organic facies adds methanol (160ml), ammonium formate (4.9g, 77.1mmol),
Catalyst palladium dydroxide, is heated to 30 DEG C of reaction 1h.TLC plate monitoring raw material reaction is complete, filters, and filtrate is concentrated to give oily
Product, adds acetonitrile (100ml), oxalic acid dihydrate (8.5g) agitation and filtration, and obtaining (9.4g, 52.3%) is white solid,
Obtain Edox-C.
Edox-C:1H-NMR(400MHz,D2O) δ 1.30 (s, 9H), 1.37-1.49 (s, 2H), 1.63 (t, 1H,
J=2.7Hz), 1.72-1.83 (m, 3H), 2.77 (s, 3H), 2.80 (t, 1H, J=12.4Hz), 2.96 (m, 3H), 3.32 (d,
1H, J=12.2Hz), 4.10 (br, 1H).
Reference example 2: synthesize by the method two in background technology
1, the synthesis of compound 2b
Compound 1 (20.4g) is dissolved in ethyl acetate (100ml), adds N-bromo-succinimide (30.22g), oxygen
Change calcium (0.96g), room temperature reaction 2 hours.TLC plate is monitored, and reaction completely, is stirred after adding sodium thiosulfate, stratification,
Aqueous phase is with ethyl acetate back extraction once.Merging organic facies, concentrating under reduced pressure, obtaining product (22.5g, 67.7%) is that off-white color is solid
Body, i.e. compound 2b.
2, the synthesis of compound 4b
Compound 2b (20g) is dissolved in acetone (125ml), adds the dimethylamine agueous solution (35.2g) of 50%, 10 DEG C of reactions
15 hours, TLC plate was monitored, and reaction completely, steams solvent, obtains grease (15.5g), i.e. compound 4b.
3, the synthesis of compound 6b
At room temperature, in compound 4b (1g), addition 28% ammonia spirit (5ml) is after 40 DEG C of stirrings 5 hours, by molten
Agent is concentrated under reduced pressure to give a grease (1.18g).After the crude product obtained is dissolved in water (5ml), at room temperature add coke
Acid di tert butyl carbonate (1.93g), 10N sodium hydrate aqueous solution (1.5ml), after 40 DEG C of stirrings 2 hours, with 4-methyl-2-
Pentanone (5ml) extracts 3 times, extractant decompression is evaporated, and adds 4-methyl-2 pentanone (3ml), at room temperature in residue
Stirring.After leaching crystallization, it is dried, obtains compound 6b (1.26g).
4, the synthesis of compound 7b
The compound 6b (214.59g) of upper step is dissolved in 4-methyl-2 pentanone (1875ml), adds MsCl (159.07g),
At room temperature, in reactant liquor, add triethylamine (170.62g), after reacting 1 hour under room temperature, in reactant liquor, add water, take
Organic facies is concentrated to give yellow solid.In residue, add 4-methyl-2 pentanone (750ml) be stirred at room temperature 3 hours, filter
Obtain white solid (242.57g), i.e. compound 7b.
5, the synthesis of Edox-C
At room temperature, Hydrazoic acid,sodium salt (7.14g) and dodecyl are added to the toluene solution (100ml) of compound 7b (20g)
Pyridinium chloride (7.80g), 60 DEG C are reacted 72 hours, obtain compound 8b, add water, the saturated chlorination of organic facies in reactant liquor
Sodium solution washs.Methanol, 10%Pd/C and ammonium formate is added in organic facies.It is heated to 40 DEG C of reaction 1h.Filtering, filtrate is dense
Contracting obtains oil product, adds acetonitrile (200ml), anhydrous ethanedioic acid acid anhydride (4.94g), is stirred at room temperature 17 hours, leaching
Crystallization.Gained crystallization adds acetonitrile (200ml), 40 DEG C of stirring 24h, and leaching is dried gained crystallization and obtains Edox-C (12.7g).
Claims (10)
1. the preparation method of Yi Zhong Yi Dushaban intermediate, it is characterised in that described Yi Dushaban intermediate is compound 5c,
Its structural formula is as follows:
This preparation method comprises the steps:
A (), with compound 1 as raw material, prepares (1S, 4S, 5S)-4-iodo-6-oxabicyclo [3.2.1]-octane-7-ketone, i.e. chemical combination
Thing 2；
B () compound 2, at uniform temperature, alkali, under solvent condition, generates noval chemical compound (1S, 3S, 6R)-7-oxabicyclo [4.1.0]
Heptane-3-carboxylic acid, i.e. compound 3c；
C () compound 3c generates noval chemical compound (1S, 3R, 4R)-3-amino-4-hydroxy under uniform temperature, solvent and aqueous ammonia conditions
Cyclohexane-carboxylic acid, i.e. compound 4c；
D () compound 4c is at uniform temperature, alkali, solvent and Bis(tert-butoxycarbonyl)oxide (Boc2O) compound 5c is generated under the conditions of；
Its reaction equation is as follows:
2. preparation method as claimed in claim 1, it is characterised in that described compound 5c prepares the step of Edox-C
Suddenly include the following:
(e) compound 5c under uniform temperature, alkali, condensing agent and solvent condition, generate the compound tert-butyl group (1R, 2R,
5S)-5-[(dimethylamino) hydroxyl]-2-hydroxy-cyclohexyl carbonyl } carbaminate, i.e. formula compound 6b；
F () is prepared Edox-C by compound 6b through compound 7b and 8b；
Its reaction equation is as follows:
3. preparation method as claimed in claim 1, it is characterised in that in step (b), described uniform temperature is 0-100 DEG C；
Described alkali is sodium hydroxide, potassium hydroxide, Lithium hydrate, one or more in potassium carbonate；Following solvent chosen by described solvent
Any one or a few: ether, methyl tertiary butyl ether(MTBE), oxolane, acetone, acetonitrile, dioxane, water.
4. preparation method as claimed in claim 3, it is characterised in that in step (b), described uniform temperature is 20 to 30 DEG C.
5. preparation method as claimed in claim 1, it is characterised in that in step (c), described uniform temperature is 0-100 DEG C；
Any one or a few of following solvent chosen by described solvent: methanol, ethanol, isopropanol, the tert-butyl alcohol, ether, methyl-tert fourth
Base ether, oxolane, acetone, acetonitrile, dioxane, water.
6. preparation method as claimed in claim 5, it is characterised in that in step (c), described uniform temperature is 30 to 50 DEG C.
7. preparation method as claimed in claim 1, it is characterised in that in step (d), described uniform temperature is-20-100 DEG C；
Described alkali includes organic base and inorganic base, and described organic base is selected from triethylamine, diisopropyl ethyl amine, pyridine, N, N-diformazan
Yl pyridines, one or more in N-methylmorpholine；Described inorganic base is selected from sodium hydroxide, potassium hydroxide, Lithium hydrate, carbon
Acid potassium, sodium bicarbonate, one or more in sodium carbonate；Any one or a few of following solvent chosen by described solvent: methanol,
Ethanol, isopropanol, the tert-butyl alcohol, ether, methyl tertiary butyl ether(MTBE), oxolane, acetone, acetonitrile, water.
8. preparation method as claimed in claim 7, it is characterised in that in step (d), described uniform temperature is 20 to 30 DEG C.
9. preparation method as claimed in claim 2, it is characterised in that in step (e), described uniform temperature is 0-100 DEG C；
Described alkali is selected from triethylamine, diisopropyl ethyl amine, pyridine, N, N-lutidines, one or more in N-methylmorpholine；
Described condensing agent is selected from carbonyl dimidazoles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxy benzo three
One or more in nitrogen azoles；Any one or a few of following solvent chosen by described solvent: halogenated hydrocarbon includes dichloromethane,
Chloroform, carbon tetrachloride, 1,2-dichloroethanes；Mystery class includes oxolane, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), methyl
Oxolane, dioxane, glycol dimethyl ether；Arene includes toluene, chlorobenzene, dimethylbenzene；Alkanes includes oil
Ether, normal heptane, normal hexane, hexamethylene；Esters includes ethyl acetate, methyl acetate, isopropyl acetate.
10. preparation method as claimed in claim 9, it is characterised in that in step (e), described uniform temperature is 20 to 30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510330875.2A CN106316889B (en) | 2015-06-15 | 2015-06-15 | Preparation method of edoxaban intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510330875.2A CN106316889B (en) | 2015-06-15 | 2015-06-15 | Preparation method of edoxaban intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106316889A true CN106316889A (en) | 2017-01-11 |
| CN106316889B CN106316889B (en) | 2020-07-10 |
Family
ID=57732113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510330875.2A Active CN106316889B (en) | 2015-06-15 | 2015-06-15 | Preparation method of edoxaban intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106316889B (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866452A (en) * | 2017-03-17 | 2017-06-20 | 浙江天宇药业股份有限公司 | The synthetic method and intermediate product of a kind of Yi Dushaban intermediates |
| CN106868088A (en) * | 2017-02-10 | 2017-06-20 | 爱斯特（成都）生物制药股份有限公司 | The method for splitting of the carboxylic acid alkyl ester isomer mixture of 7 oxabicyclos [4.1.0] heptane 3 |
| CN108689878A (en) * | 2017-04-10 | 2018-10-23 | 浙江九洲药业股份有限公司 | The preparation method of optical activity diamino radical derivative |
| CN109942600A (en) * | 2019-04-15 | 2019-06-28 | 内蒙古京东药业有限公司 | A kind of preparation method of Yi Dushaban |
| CN111606826A (en) * | 2020-07-02 | 2020-09-01 | 沧州那瑞化学科技有限公司 | Preparation method of edoxaban intermediate |
| CN111606827A (en) * | 2020-06-23 | 2020-09-01 | 内蒙古京东药业有限公司 | Method for preparing chiral amine intermediate of edoxaban |
| CN111763157A (en) * | 2020-04-26 | 2020-10-13 | 中山大学 | Chiral amino compound, preparation method and application thereof, and preparation method for preparing edoxaban intermediate from chiral amino compound |
| WO2022028007A1 (en) * | 2020-08-03 | 2022-02-10 | 珠海市海瑞德新材料科技有限公司 | Intermediate for preparing edoxaban free base, preparation method therefor, and application thereof |
| WO2022152315A1 (en) * | 2021-01-18 | 2022-07-21 | 海创药业股份有限公司 | Synthesis method for aminopyrimidine fak inhibitor compound |
| CN115583900A (en) * | 2022-04-29 | 2023-01-10 | 张邦成都生物医药科技有限公司 | Preparation method of high-purity ixaban intermediate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101263110A (en) * | 2005-09-16 | 2008-09-10 | 第一三共株式会社 | Optically active diamine derivative and process for producing the same |
| CN102348688A (en) * | 2009-03-10 | 2012-02-08 | 第一三共株式会社 | Process for producing diamine derivative |
| CN102348680A (en) * | 2009-03-13 | 2012-02-08 | 第一三共株式会社 | Method for producing optically active diamine derivative |
| CN102516249A (en) * | 2011-12-08 | 2012-06-27 | 成都苑东药业有限公司 | Anticoagulant diamine derivative |
| CN103080078A (en) * | 2010-07-02 | 2013-05-01 | 第一三共株式会社 | Process for preparation of optically active diamine derivative salt |
| WO2014081047A1 (en) * | 2012-11-23 | 2014-05-30 | Daiichi Sankyo Company,Limited | Process for the preparation of (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1] octan-7-one |
| WO2014157653A1 (en) * | 2013-03-29 | 2014-10-02 | 第一三共株式会社 | Processes for preparing optically active diamine derivatives |
| WO2014157612A1 (en) * | 2013-03-29 | 2014-10-02 | 第一三共株式会社 | Method for producing (1s,4s,5s)-4-bromo-6- oxabicyclo[3.2.1]octane-7-one |
-
2015
- 2015-06-15 CN CN201510330875.2A patent/CN106316889B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101263110A (en) * | 2005-09-16 | 2008-09-10 | 第一三共株式会社 | Optically active diamine derivative and process for producing the same |
| CN102348688A (en) * | 2009-03-10 | 2012-02-08 | 第一三共株式会社 | Process for producing diamine derivative |
| CN102348680A (en) * | 2009-03-13 | 2012-02-08 | 第一三共株式会社 | Method for producing optically active diamine derivative |
| CN103080078A (en) * | 2010-07-02 | 2013-05-01 | 第一三共株式会社 | Process for preparation of optically active diamine derivative salt |
| CN102516249A (en) * | 2011-12-08 | 2012-06-27 | 成都苑东药业有限公司 | Anticoagulant diamine derivative |
| WO2014081047A1 (en) * | 2012-11-23 | 2014-05-30 | Daiichi Sankyo Company,Limited | Process for the preparation of (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1] octan-7-one |
| WO2014157653A1 (en) * | 2013-03-29 | 2014-10-02 | 第一三共株式会社 | Processes for preparing optically active diamine derivatives |
| WO2014157612A1 (en) * | 2013-03-29 | 2014-10-02 | 第一三共株式会社 | Method for producing (1s,4s,5s)-4-bromo-6- oxabicyclo[3.2.1]octane-7-one |
Non-Patent Citations (2)
| Title |
|---|
| 刘永强等: ""依度沙班对甲苯磺酸盐一水合物合成路线图解"", 《中国新药杂志》 * |
| 潘林玉等: ""依度沙班合成路线图解"", 《中国医药工业杂志》 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106868088A (en) * | 2017-02-10 | 2017-06-20 | 爱斯特（成都）生物制药股份有限公司 | The method for splitting of the carboxylic acid alkyl ester isomer mixture of 7 oxabicyclos [4.1.0] heptane 3 |
| CN106868088B (en) * | 2017-02-10 | 2020-07-14 | 爱斯特（成都）生物制药股份有限公司 | Resolution method of isomer mixture of 7-oxabicyclo [4.1.0] heptane-3-carboxylic acid alkyl ester |
| CN106866452A (en) * | 2017-03-17 | 2017-06-20 | 浙江天宇药业股份有限公司 | The synthetic method and intermediate product of a kind of Yi Dushaban intermediates |
| CN108689878A (en) * | 2017-04-10 | 2018-10-23 | 浙江九洲药业股份有限公司 | The preparation method of optical activity diamino radical derivative |
| CN108689878B (en) * | 2017-04-10 | 2023-05-09 | 浙江九洲药业股份有限公司 | Process for preparing optically active diamino derivatives |
| CN109942600B (en) * | 2019-04-15 | 2021-08-20 | 内蒙古京东药业有限公司 | Preparation method of edoxaban |
| CN109942600A (en) * | 2019-04-15 | 2019-06-28 | 内蒙古京东药业有限公司 | A kind of preparation method of Yi Dushaban |
| CN111763157A (en) * | 2020-04-26 | 2020-10-13 | 中山大学 | Chiral amino compound, preparation method and application thereof, and preparation method for preparing edoxaban intermediate from chiral amino compound |
| CN111606827A (en) * | 2020-06-23 | 2020-09-01 | 内蒙古京东药业有限公司 | Method for preparing chiral amine intermediate of edoxaban |
| CN111606826B (en) * | 2020-07-02 | 2022-02-22 | 沧州那瑞化学科技有限公司 | Preparation method of edoxaban intermediate |
| CN111606826A (en) * | 2020-07-02 | 2020-09-01 | 沧州那瑞化学科技有限公司 | Preparation method of edoxaban intermediate |
| WO2022028007A1 (en) * | 2020-08-03 | 2022-02-10 | 珠海市海瑞德新材料科技有限公司 | Intermediate for preparing edoxaban free base, preparation method therefor, and application thereof |
| WO2022152315A1 (en) * | 2021-01-18 | 2022-07-21 | 海创药业股份有限公司 | Synthesis method for aminopyrimidine fak inhibitor compound |
| CN114805308A (en) * | 2021-01-18 | 2022-07-29 | 海创药业股份有限公司 | Method for synthesizing aminopyrimidine FAK inhibitor compound |
| CN115583900A (en) * | 2022-04-29 | 2023-01-10 | 张邦成都生物医药科技有限公司 | Preparation method of high-purity ixaban intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106316889B (en) | 2020-07-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106316889A (en) | Preparation method of Edoxaban intermediate | |
| CA2928242C (en) | Process for the preparation of a pde4 inhibitor | |
| AU2014339136A1 (en) | Process for the preparation of a PDE4 inhibitor | |
| CN108947891A (en) | The method for safely preparing a Mo Fanselin and its tartrate using triphosgene | |
| CN108794351A (en) | A kind of preparation method of Mo Fanselin key intermediate | |
| EP3872081A1 (en) | Preparation method for deuterated macrocyclic compound | |
| CN114437031A (en) | Synthetic method of 6-methyl nicotine | |
| KR20130004296A (en) | Processes for making cyclopropyl amide derivatives and intermediates associated therewith | |
| EP3137449B1 (en) | Process for the preparation of substituted cycloserines | |
| CA3137007A1 (en) | Process for preparing carbamoyloxymethyl triazole cyclohexyl acid compounds | |
| JP6748329B1 (en) | Crystal form of sofupyronium bromide and method for producing the same | |
| CN104136422B (en) | The process for purification of compound, the manufacture method of compound and compound | |
| EP4289828A1 (en) | Method for the preparation of a 3,6-dihydro-2h-1,3,4-oxadiazin-2-one | |
| CN106588841B (en) | The method for synthesizing 2,3- dihydro -1- benzofuran -4- formaldehyde | |
| JP7457940B2 (en) | Method for producing 1-(1-tert-butoxycarbonyl-4-piperidylacetyl)-4-mesyloxypiperidine and 1-(1-tert-butoxycarbonyl-4-piperidylacetyl)-4-mesyloxypiperidine | |
| CN103922996B (en) | A kind of drug new intermediate and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210820 Address after: No. 1, Hengfei Road, Xingang economic and Technological Development Zone, Nanjing, Jiangsu 210038 Patentee after: Nanjing Changao Pharmaceutical Science & Technology Co.,Ltd. Address before: 201203 4th floor, building 7, Lane 1690, Cailun Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee before: Shanghai Sun-Sail Pharmaceutical Science & Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right |