CN107434780A - A kind of AR-13324 preparation method - Google Patents
A kind of AR-13324 preparation method Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
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Abstract
The present invention relates to a kind of AR 13324 preparation method, the present invention utilizes chiral ligand chiral induction synthesis AR 13324, compared with existing chiral HPLC methods or SFC methods, AR 13324, which is prepared, using the method for chemical synthesis has the characteristics of simple to operate, synthesis condition is simple, cost is low, high-purity obtains chiral monomer, and high income.
Description
Technical field
The present invention relates to field of medicaments, and in particular to ROCK kinases and norepinephrine transporter inhibitor, more specifically
The preparation method for being related to AR-13324 inhibitor.
Background technology
AR-13324 is ROCK kinases and norepinephrine transporter inhibitor.Generally pass through chirality in existing method
Prepared by HPLC methods or SFC methods, HPLC methods are current common methods, but the cost of chiral stationary phase is too high, chirality stream
Dynamic phase additive complicates chromatographic condition；AR-13324 is prepared using SFC (supercritical fluid chromatography) and the problem of same be present,
Not only cost is high but also yield is also low.
The content of the invention
It is an object of the invention to provide a kind of AR-13324 simple to operate, cost is low preparation method.
The concrete technical scheme of the present invention is as follows：
A kind of AR-13324 preparation method, AR-13324, the knot of chiral ligand are synthesized using chiral ligand chiral induction
Structure formula is as shown in Equation 5：
X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxybenzenes
Base, A are oxygen or sulphur.
The synthesis step of preferable chiral ligand is as follows：
(1) hydroxyl in 4- (hydroxymethyl) phenylacetic acid is protected by TBSCl or TIPSCl, obtains crude product chemical combination
Thing 4；
X is OTBS, OTIPS,
(2) compound 4, asymmetric syntheses chiral auxiliary are dissolved in organic solvent, add oxalyl chloride, dry ice acetone drop
Temperature, reacted under catalyst action and obtain chiral ligand, the structural formula of chiral ligand is as shown in Equation 5：
X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxybenzenes
Base, A are oxygen or sulphur.
Preferably comprised the following steps using chiral ligand chiral induction synthesis AR-13324：
(1) hydroxyl in 4- (hydroxymethyl) phenylacetic acid is protected by TBSCl or TIPSCl, obtains crude product chemical combination
Thing 4；
X is OTBS, OTIPS,
(2) compound 4, asymmetric syntheses chiral auxiliary are dissolved in organic solvent, add oxalyl chloride, dry ice acetone drop
Temperature, reacted under catalyst action and obtain chiral ligand, the structural formula of chiral ligand is as shown in Equation 5：
X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxybenzenes
Base, A are oxygen or sulphur,
(3) compound 5, hmds sodium, compound 13 are dissolved in organic solvent, dry ice acetone cooling, stirring
Reaction, then heats to room temperature and is stirred overnight, and obtains crude Compound 6, crosses post and purifies to obtain sterling compound 6；
X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxybenzenes
Base, A are oxygen or sulphur,
(4) compound 6 is added in organic solvent and water, frozen water cooling, then adds lithium hydroxide, stirring reaction, adjust
PH value is saved, decompression steams organic solvent and then filtering, and filtrate is through extracting, drying, evaporated under reduced pressure obtains compound 7；
X is OTBS, OTIPS
(5) compound 7, I-hydroxybenzotriazole, triethylamine are added in dry methylene chloride, nitrogen protection, cooling,
Add EDCI into reaction solution, heating stirring, reaction solution evaporated under reduced pressure then added into frozen water into residue to solvent-free,
PH is adjusted, compound 7A is obtained through extracting, purifying；
X is OTBS, OTIPS
(6) compound 7A, 6- aminoisoquinoline and EDCI are added in pyridine, nitrogen protection, then adds 4- diformazan ammonia
Yl pyridines, overnight, evaporated under reduced pressure obtains compound 8 after reacting completely for reaction；
X is OTBS, OTIPS,
(7) compound 8 is dissolved in organic solvent, adds hydrazine hydrate thereto, be heated to flowing back, it is cold after the completion of reaction
But, filter, obtain compound 9；
X is OTBS, OTIPS,
(8) it is introduced into tertbutyloxycarbonyl to protect the amino in compound 9, obtains compound 10；
X is OTBS, OTIPS,
(9) compound 10 is added in organic solvent, then adds tetrabutyl ammonium fluoride and reacted, subtracted after the completion of reaction
Pressure is evaporated, and obtains compound 11；
(10) 2,4- mesitylenic acids and dimethylformamide are added in toluene, cooled down, add oxalyl chloride, heating is anti-
Evaporated under reduced pressure obtains yellow oil, is dissolved in obtaining the solution of acid chloride of dichloromethane in dichloromethane after the completion of should, reacting；
By compound 11, triethylamine, it is added in dichloromethane, nitrogen protection, the acyl chlorides for then adding dichloromethane is molten
Liquid, evaporated under reduced pressure after the completion of reaction, compound 12 is obtained after then scrubbed, filtering；
(11) compound 12 is dissolved in dichloromethane, then adds the hydrogen chloride solution of methanesulfonic acid or Isosorbide-5-Nitrae-dioxane
Stir at room temperature, vacuum rotary steam, be filtrated to get AR-13324 mesylates or hydrochloride；
It is preferred that step (2) in, compound 4 is dissolved in anhydrous tetrahydro furan, -8~-12 DEG C is cooled to, is slowly added dropwise
Oxalyl chloride, insulation, obtains acyl chlorides；Asymmetric syntheses chiral auxiliary is added in anhydrous tetrahydro furan in addition simultaneously, with dry ice third
Ketone is cooled to -78 DEG C, adds n-BuLi, insulated and stirred, then adds acyl chlorides and continue reaction 1~3 hour, be warming up to room temperature and stir
Mix overnight；Terminating reaction, tetrahydrofuran solvent is removed, residue is through extracting, washing, being dried to obtain crude Compound 5, after purification
Obtain sterling compound 5；The compound 4 of addition is 0.8~1.3 with the mol ratio of asymmetric syntheses chiral auxiliary:1, compound 4
Mol ratio with oxalyl chloride is 1~2:1.
It is preferred that step (3) in, compound 5 is dissolved in anhydrous tetrahydro furan, dry ice acetone is cooled to -78 DEG C
Degree, adds hmds sodium insulation reaction 0.5~1.5 hour；Compound 13 is dissolved in before being added after anhydrous tetrahydro furan
State in reaction system, insulation reaction 2~4 hours, warm naturally to room temperature and be stirred overnight, solvent tetrahydrochysene is removed after reacting completely
Furans, residue obtain sterling compound 6 after purification through extracting, washing, being dried to obtain crude Compound 6；The compound of addition
5 with the mol ratio of hmds sodium be 16~17:20, the compound 5 of addition is 17~18 with the mol ratio of compound 13:
20。
It is preferred that step (4) in, compound 6 is added in organic solvent and water, frozen water is cooled to 0 DEG C, then adds hydrogen
Lithia stirring reaction 2.5~3.5 hours, decompression steam organic solvent and then filtering, and filtrate is through extracting, drying, evaporated under reduced pressure
Obtain compound 7；The compound 6 of addition is 0.5~1.5 with the mol ratio of lithium hydroxide:3, the volume ratio of organic solvent and water
For 1~3:1.
It is preferred that step (5) in, compound 7, I-hydroxybenzotriazole, triethylamine are added in dry methylene chloride,
Nitrogen is protected, and is cooled to 0 DEG C, EDCI is added into reaction solution, be warming up to and be stirred at room temperature, and reaction overnight, then subtracts reaction solution
Pressure is evaporated to solvent-free, and frozen water is added into residue, adjusts pH to 3-4, compound 7A is obtained through extracting, purifying；Add
Compound 7 and the mol ratio of I-hydroxybenzotriazole are 0.8~1.3:1, the compound 7 of addition is 0.7 with EDCI mol ratio
~1:1, the mol ratio of compound 7 and triethylamine is 0.2~0.3:1.
It is preferred that step (6) in, the compound 7A of addition and the mol ratio of 6- aminoisoquinolines are 4.5~5.5:6, add
Compound 7A and EDCI mol ratio be 4.5~5.5:6.
It is preferred that step (7) in, be cooled to 4~6 DEG C, the compound 8 of addition and the mol ratio of hydrazine hydrate be 0.05~
0.2:1。
It is preferred that step (8) in, compound 9 is dissolved in dichloromethane, then adds triethylamine and two dimethyl dicarbonate fourths
Ester is reacted, and evaporated under reduced pressure after the completion of reaction, obtains compound 10；The compound 9 and the mol ratio of triethylamine of addition be
0.06~0.08:1, the compound 9 of addition is 66~68 with the mol ratio of di-tert-butyl dicarbonate:1.
In step (9), the addition of tetrabutyl ammonium fluoride is not specially required, is using the amount of being routinely added in the art
Can.
It is preferred that step (10) in, 2,4- mesitylenic acids and dimethylformamide are dissolved in toluene, are cooled to 2-5
DEG C, room temperature is warming up to after adding oxalyl chloride, is stirred overnight, evaporated under reduced pressure obtains yellow oil, is dissolved in dichloromethane
The solution of acid chloride of dichloromethane is obtained, 2, the 4- mesitylenic acids of addition and the mol ratio of oxalyl chloride are 9~11:13；
Compound 11, triethylamine are added in dichloromethane, nitrogen protection, are then slowly added to dichloromethane in 0-5 DEG C
The solution of acid chloride of alkane is reacted, evaporated under reduced pressure after the completion of reaction, and compound 12 is obtained after then scrubbed, filtering, addition
The mol ratio of 2,4- mesitylenic acid of the compound 11 with adding is 0.7~0.8:1.
It is preferred that step (11) in, the compound 12 of addition and the mol ratio of methanesulfonic acid are 0.5~1.5:3；1,4- dioxies
The molar concentration of hydrogen chloride is 3.5~4.5mol/L in the hydrogen chloride solution of six rings；Compound 12 and the chlorine of 1,4- dioxane
The mol ratio for changing hydrogen chloride in hydrogen solution is 0.1~0.15:1.
Organic solvent in the present invention can use Isosorbide-5-Nitrae-dioxane, methanol, ethanol, one kind in isopropanol.
The present invention is using chiral ligand chiral induction synthesis AR-13324, with existing chiral HPLC methods or SFC method phases
Than, AR-13324, which is prepared, using the method for chemical synthesis has the characteristics of simple to operate, synthesis condition is simple, cost is low,
High-purity obtains chiral monomer, and high income.
Brief description of the drawings
Fig. 1 is the 1HNMR spectrograms of AR-13324 hydrochlorides.
Embodiment
" TLC " of the present invention refers to thin-layer chromatography (Thin Layer Chromatography), also known as thin-layer chromatography.
EDCI in the present invention refers to 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides.
The molar concentration of hydrogen chloride refers to HCl gases being dissolved in 1,4- bis- in the hydrogen chloride solution of 1,4- dioxane
Concentration in the ring of oxygen six, as Isosorbide-5-Nitrae-dioxane hydrogen chloride solution in the molar concentration of hydrogen chloride refer to 4mol HCl for 4mol/L
Gas is dissolved in 1L dioxane.
The present invention is further illustrated with reference to embodiments, and the present invention does not refer to that part is prior art.
Embodiment 1
Synthesize compound 2
50g compounds 1 (4- methylphenyl acetic acids) are dissolved in 200 milliliters of carbon tetrachloride, are heated to flowing back, under heated condition
NBS (N- bromo-succinimides) (62g, 0.35mol) is added portionwise, continues to keep reflux state to continue 3 hours after adding, has
A large amount of solids separate out, and TLC shows that raw material reaction is complete, and reaction solution is cooled into room temperature, 500 milliliters of ice are poured under stirring
In water, continue stirring 20 minutes, filtering, filter cake is washed with water 3 times (every time 300 milliliters), white solid is obtained, by white solid
51g compounds 2 (4- bromomethyls phenylacetic acid) are obtained within 10 hours in 50 DEG C of drying, compound 2 is not required to continue to purify directly to carry out down
Single step reaction.
Synthesize compound 3
Compound 2 (50g) is added in 200 milliliters of water, is heated with stirring to and is flowed back and kept for 2 hours, reaction becomes clarification,
Room temperature is subsequently cooled to, ice bath is cooled to 2 degree or so, separates out white solid, filtering, and filter cake is washed with water 2 times and obtains white admittedly
Body, white solid is obtained into about 33 g of compound 3 in 10 hours in 50 DEG C of drying.
Synthesize compound 4
Compound 3 (30g) and imidazoles (18.5g) are dissolved in 300 milliliters of DMF, ice bath is cooled to 0 degree, is added portionwise
TBSCl (32.65g), warms naturally to room temperature and is stirred overnight, and TLC shows that raw material is wholly absent, and ice bath is cooled to 0 DEG C or so,
Reaction is quenched with saturated aqueous ammonium chloride, and pH value is adjusted to 3~4 with 1M watery hydrochloric acid, is warming up to and half an hour is stirred at room temperature, use
Methyl tertiary butyl ether(MTBE) extracts 3 times (every time 200 milliliters), merges organic phase saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter is spin-dried for obtaining crude Compound 4 (46g), and the crude product is not required to be further purified to be directly used in react in next step.
Synthesize compound 5 (chiral ligand)
Compound 4 (40g, 142.64mmol) to be dissolved in anhydrous tetrahydro furan (500 milliliters), dry ice acetone is cooled to-
10 degree, oxalyl chloride (11.0g) is slowly added dropwise, keeps dropping temperature that acyl chlorides is prepared not higher than -10 degree；Simultaneously other one
21.16g (R) -4- phenyl -2- oxazolidones are added in 500 milliliters of anhydrous tetrahydro furans in individual there-necked flask, nitrogen displacement, used
Dry ice acetone is cooled to -78 degree, and n-BuLi (2.5M, 60ml) is slowly added dropwise and maintains the temperature at -78 degree, is added dropwise to complete follow-up
Continue and stirred 1 hour under -78 degree, acyl chlorides prepared above is then slowly added dropwise by constant pressure funnel, keep dropping temperature -78
Degree, continue to keep -78 degree reaction 2 hours after being added dropwise to complete, then warm naturally to be stirred overnight at room temperature.With saturated ammonium chloride water
Reaction is quenched in solution, and revolving removes tetrahydrofuran solvent, residue with Ethyl acetate extraction 3 times (each 300ml), merged organic
Saturated common salt water washing, anhydrous sodium sulfate drying are mutually used, filtering is spin-dried for obtaining crude Compound 5, crosses post and purifies to obtain sterling
Compound 5 (40.5g), yield 73.39%.
Synthesize compound 6
Sterling compound 5 (40g, 94mmol) is dissolved in anhydrous tetrahydro furan (400ml), nitrogen displacement, dry ice acetone
Be cooled to -78 degree, be slowly added dropwise hmds sodium tetrahydrofuran solution (112.8mmol, hmds sodium it is dense
Spend for 2mol/L), rear system is added dropwise to complete in the lower stirring of -78 degree 1 hour；Compound 13 (108mmol) be dissolved in 400 milliliters it is anhydrous
In tetrahydrofuran (THF), slowly it is added dropwise in foregoing system by constant pressure funnel, control dropping temperature is less than -70 degree, completion of dropwise addition
Reaction is maintained at the lower stirring of -78 degree 3 hours afterwards, warms naturally to room temperature and is stirred overnight.TLC shows that raw material reaction is complete, uses
Reaction is quenched in 500 milliliters of saturated aqueous ammonium chloride, and revolving removes solvents tetrahydrofurane, and residue with Ethyl acetate extracts 3 times
(every time 200 milliliters), merge organic phase saturated common salt water washing, anhydrous sodium sulfate drying, and filtering is spin-dried for obtaining crude product chemical combination
Thing 6, cross post and purify to obtain sterling compound 6 (43g), yield (78.24%).
Synthesize compound 7
Sterling compound 6 (29.2g, 0.05mol) is added in 300ml tetrahydrofurans and 100ml water, frozen water cooling reaction
Then system adds lithium hydroxide (6.3g, 0.15mol) to 0 DEG C, stirred 3 hours in 0 DEG C.LC-MS monitoring is reacted to compound
6 disappear, and decompression, which steams organic solvent, has a large amount of white solids to separate out, filtering, at room temperature adjust filtrate with 1N aqueous hydrochloric acid solution
PH to 3-4, ethyl acetate (100ml) are extracted four times, and sodium sulphate is dried, and evaporated under reduced pressure obtains white foam solid 20.1g, do not entered
One step purifies, and is directly used in next step, purity 94.5%.
Synthesize compound 7A
By compound 7 (22.5g, 0.05mol), HOBT (I-hydroxybenzotriazole) (6.75g, 0.05mol) and triethylamine
(25ml) adds dry methylene chloride (300ml), nitrogen protection, is cooled to 0 DEG C, EDCI is then added into reaction solution
(22.5g, 0.05mol), stirring a period of time, reaction solution become clarification, are to slowly warm up to room temperature, reaction is overnight.Reaction solution is subtracted
Pressure is evaporated to solvent-free, the addition 200ml frozen water into residue, adjust pH to 2-3, EA to extract with the aqueous hydrochloric acid solution of ice-cold mistake,
Cross post purifying (dichloromethane：Methanol=20:1-10:1) compound 7A (18.65g) white foam solid, yield are obtained
85%；LC-MS(M-1)438.
Synthesize compound 8
At room temperature by compound 7A (10.9g, 25mmol), 6- aminoisoquinolines (4.32g, 30mmol) and EDCI
(6.68g, 35mmol) is added in pyridine (100ml), nitrogen protection, then add DMAP (DMAP) (4.2g,
35mmol), reaction is stayed overnight, TLC (DCM:MA=20:1) monitoring is reacted to starting compound 7A and disappeared, evaporated under reduced pressure, 3 moles
PH=4-5 is arrived in aqueous acetic acid regulation, DCM (100ml*4) extractions, was merged post and is obtained compound 8 (11.02g), yield
78%；LC-MS (M+1) 566, purity：97.4%.
Synthesize compound 9
By compound 8 (11.02g, 19.5mmol) with ethanol (100ml) dissolve, thereto add hydrazine hydrate (85%,
9.75g, 195mmol), it is heated to flowing back, about 2 as a child there are a large amount of white solids to generate afterwards, then proceeded to reaction 3 hours, cold
But to 5 degree, filtering, filter cake washs with cold ethanol, evaporated under reduced pressure, is decompressed to oil pump solvent-free, obtains compound 9 (11.4g),
It is directly used in next step.
Synthesize compound 10
The compound 9 (11.4g, 19.5mmol) that upper step obtains is dissolved in 100ml dichloromethane, then added thereto
Entering triethylamine (10ml), (BOC) 2O (di-tert-butyl dicarbonate) (6.4g, 0.29mmol), which is slowly added dropwise, has a large amount of gases to release,
TLC (ethyl acetate) monitoring reaction to compound 9 disappears, evaporated under reduced pressure, column chromatography (EA:PE=1:1) white solid production is obtained
Thing (9.49g), as compound 10, yield：90%.
Synthesize compound 11
The compound 10 (8g, 15mmol) that upper step is obtained is added in 100ml THF (tetrahydrofuran), is then added thereto
Enter tetrabutyl ammonium fluoride (7.83g, 30mmol), be stirred overnight, TLC (EA) detections reaction is remaining without compound 10, evaporated under reduced pressure
Thing adds 200ml water, stirs 30min, static a period of time, removes water, and tan solid is dissolved in into sodium sulphate in EA dries,
Remove organic solvent and obtain compound 11 (7.86g), for further processing, be directly used in next step.
Synthesize compound 12
The DMF of 2,4- mesitylenic acids (1.5g, 10mmol) and catalytic amount is added in toluene, is cooled to 2-5 DEG C, drop
Add oxalyl chloride (1.64g, 13mmol), be warming up to room temperature after dripping, be stirred overnight, in the process solid gradually dissolve one
Clarified solution, evaporated under reduced pressure obtain a yellow oil, and the solution of acid chloride of dichloromethane is obtained with dichloromethane (10ml) dissolving；
Compound 11 (3.2g, 7.7mmol) and triethylamine (2ml) are added in 20ml dichloromethane, nitrogen protection will be upper
The solution of acid chloride for stating the dichloromethane being prepared instills at 0-5 DEG C, is stirred after adding, and reaction is overnight；TLC (dichloromethane：
Methanol=20:1) monitoring reaction, reaction are finished, evaporated under reduced pressure, then stirred with saturated sodium carbonate solution, are filtered, filter cake water
Washing 3 times, drying obtain 3.9g white solids, as compound 12；Purity：99.1%, optical purity：100%
(CHIRALPAK AS-H, 0.46cm I.D. × 15cm L, MeOH+0.1DEA)/CO2=20/80 (V/V, 2.0ml/min), R
Type, Rt=3.253min；S types Rt=4.3min).
Compound 12 (3.9g) is added in DCM, stirs to obtain clarified solution, the chlorine of Isosorbide-5-Nitrae-dioxane is then added dropwise thereto
Change hydrogen solution 15ml (concentration 4mol/L, 4mol HCl gases are dissolved in 1L dioxane), it is small to be then stirred at room temperature 4
When, vacuum rotary steam, 3.65g white solid products are filtered to obtain, it is AR-13324 hydrochlorides to detect gained material through HNMR, its
1HNMR spectrograms are shown in Figure 1, MS, purity, 99.4%, 1HNMR (400MHz, DMSO, 300) δ (ppm).11.773(s,
1H),9.702(s,1H),8.740(d,1H),8.560(d,1H),8.469(d,1H),8.360(d,1H),8.280(s,3H),
8.158(dd,1H),7.777(d,1H),7.577(d,2H),7.496(d,2H),7.134(s,1H),7.111(d,1H),
5.281(s,2H),4.504(q,1H),3.609(q,1H),3.139(q,1H),2.483(s,3H),2.302(s,3H)。
The structural formula of AR-13324 hydrochlorides is as described below：
Embodiment 2
In the embodiment, in addition to different to the processing step of compound 12, remaining is same as Example 1.
It is as follows to the processing step of compound 12：Compound 12 (3.9g) is dissolved in 40ml dichloromethane, is then added dropwise
Methanesulfonic acid (2g, 21.6mmol), is stirred at room temperature overnight, vacuum rotary steam, adds 100ml ether thereto, stirring, produces big
White solid is measured, filtering, dries and obtains white solid (4.54g), yield, 97.8%, purity 98.2%, institute is detected through 1HNMR
It is AR-13324 mesylates to obtain material.
Embodiment 3
In the embodiment, in addition to the synthesis step of compound 5 is different, remaining is same as Example 1.
Synthesize compound 5A (chiral ligand)
Compound 4 (50g, 178.3mmol) is dissolved in anhydrous tetrahydro furan (500 milliliters), and dry ice acetone is cooled to -10
Degree, oxalyl chloride (13g) is slowly added dropwise, keeps dropping temperature to obtain acyl chlorides not higher than -10 degree；Simultaneously in another there-necked flask
It is middle to add 28.7g (R) -4- benzyl -2- oxazolidones in 500 milliliters of anhydrous tetrahydro furans, nitrogen displacement, dropped with dry ice acetone
Temperature is slowly added dropwise 7.2ml n-butyllithium solutions (concentration 2.5mol/L) and maintains the temperature at -78 degree, be added dropwise to complete to -78 degree
After continue -78 degree under stir 1 hour, acyl chlorides prepared above is slowly added drop-wise in the there-necked flask by constant pressure funnel, guarantor
Hold dropping temperature to spend -78, reacted after being added dropwise to complete and continue to keep -78 degree 2 hours, then warm naturally to be stirred at room temperature
Night.Reaction is quenched with saturated aqueous ammonium chloride, revolving removes tetrahydrofuran solvent, and residue with Ethyl acetate extracts 3 times (often
Secondary 300ml), merge organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filtering is spin-dried for obtaining crude Compound 5A,
Post is crossed to purify to obtain sterling 5A (50g), yield 70.13%.
The synthetic route of embodiment 3 is as follows：
Claims (10)
- A kind of 1. AR-13324 preparation method, it is characterised in that AR-13324 is synthesized using chiral ligand chiral induction, it is chiral The structural formula of part is as shown in Equation 5：X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxyphenyls, A For oxygen or sulphur.
- 2. preparation method according to claim 1, it is characterised in that the synthesis step of chiral ligand is as follows：(1) pass through TBSCl or TIPSCl protects to the hydroxyl in 4- (hydroxymethyl) phenylacetic acid, obtains crude Compound 4；X is OTBS, OTIPS,(2) compound 4, asymmetric syntheses chiral auxiliary being dissolved in organic solvent, adds oxalyl chloride, dry ice acetone cools, Reaction obtains chiral ligand under catalyst action, and the structural formula of chiral ligand is as shown in Equation 5：X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxyphenyls, A are oxygen or sulphur.
- 3. preparation method according to claim 1 or 2, it is characterised in that synthesize AR- using chiral ligand chiral induction 13324 comprise the following steps：(1) hydroxyl in 4- (hydroxymethyl) phenylacetic acid is protected by TBSCl or TIPSCl, obtains crude Compound 4；X is OTBS, OTIPS,(2) compound 4, asymmetric syntheses chiral auxiliary being dissolved in organic solvent, adds oxalyl chloride, dry ice acetone cools, Reaction obtains chiral ligand under catalyst action, and the structural formula of chiral ligand is as shown in Equation 5：X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxyphenyls, A are oxygen or sulphur；(3) compound 5, hmds sodium, compound 13 are dissolved in organic solvent, dry ice acetone cooling, stirring reaction, Then heat to room temperature and be stirred overnight, obtain crude Compound 6, cross post and purify to obtain sterling compound 6；X is OTBS, OTIPS, Y Ph, Bn, t-bu, 4- nitrobenzophenone or 4- methoxyphenyls, A For oxygen or sulphur；(4) compound 6 is added in organic solvent and water, frozen water cooling, then adds lithium hydroxide, stirring reaction, adjust PH Value, decompression steam organic solvent and then filtering, and filtrate is through extracting, drying, evaporated under reduced pressure obtains compound 7；X is OTBS, OTIPS；(5) compound 7, I-hydroxybenzotriazole, triethylamine are added in dry methylene chloride, nitrogen protection, cooling, to anti- Answer and EDCI is added in liquid, heating stirring, reaction solution evaporated under reduced pressure is then added into frozen water into residue to solvent-free, adjusted PH, compound 7A is obtained through extracting, purifying；X is OTBS, OTIPS；(6) compound 7A, 6- aminoisoquinoline and EDCI are added in pyridine, nitrogen protection, then adds 4- dimethylamino pyrroles Pyridine, overnight, evaporated under reduced pressure obtains compound 8 after reacting completely for reaction；X is OTBS, OTIPS；(7) compound 8 is dissolved in organic solvent, adds hydrazine hydrate thereto, be heated to flowing back, cooled down after the completion of reaction, mistake Filter, obtains compound 9；X is OTBS, OTIPS；(8) it is introduced into tertbutyloxycarbonyl to protect the amino in compound 9, obtains compound 10；X is OTBS, OTIPS；(9) compound 10 is added in organic solvent, then adds tetrabutyl ammonium fluoride and reacted, depressurized and steam after the completion of reaction It is dry, obtain compound 11；(10) 2,4- mesitylenic acids and dimethylformamide are added in toluene, cooled down, addition oxalyl chloride, temperature reaction, Evaporated under reduced pressure obtains yellow oil, is dissolved in obtaining the solution of acid chloride of dichloromethane in dichloromethane after the completion of reaction；By compound 11, triethylamine, it is added in dichloromethane, nitrogen protection, then adds the solution of acid chloride of dichloromethane, instead Evaporated under reduced pressure after the completion of answering, compound 12 is obtained after then scrubbed, filtering；(11) compound 12 is dissolved in dichloromethane, then adds the hydrogen chloride solution of methanesulfonic acid or Isosorbide-5-Nitrae-dioxane in room Temperature is lower to be stirred, and vacuum rotary steam, is filtrated to get AR-13324 mesylates or hydrochloride；
- 4. preparation method according to claim 3, it is characterised in that in step (2), compound 4 is dissolved in anhydrous tetrahydrochysene furan In muttering, -8~-12 DEG C are cooled to, oxalyl chloride is slowly added dropwise, is incubated, obtains acyl chlorides；Asymmetric syntheses chirality is helped in addition simultaneously Agent is added in anhydrous tetrahydro furan, is cooled to -78 DEG C with dry ice acetone, is added n-BuLi, insulated and stirred, then add acyl chlorides Continue reaction 1~3 hour, be warming up to and be stirred overnight at room temperature；Terminating reaction, tetrahydrofuran solvent is removed, residue is through extracting, washing Wash, be dried to obtain crude Compound 5, obtain sterling compound 5 after purification；The compound 4 of addition helps with asymmetric syntheses chirality The mol ratio of agent is 0.8~1.3:1, the mol ratio of compound 4 and oxalyl chloride is 1~2:1.
- 5. preparation method according to claim 4, it is characterised in that in step (3), compound 5 is dissolved in into anhydrous tetrahydrochysene furan In muttering, dry ice acetone is cooled to -78 DEG C of degree, adds hmds sodium insulation reaction 0.5~1.5 hour；By chemical combination Thing 13 is added in previous reaction system after being dissolved in anhydrous tetrahydro furan, insulation reaction 2~4 hours, is warmed naturally to room temperature and is stirred Mix overnight, solvents tetrahydrofurane is removed after reacting completely, residue purifies through extracting, washing, being dried to obtain crude Compound 6 After obtain sterling compound 6；The compound 5 of addition is 16~17 with the mol ratio of hmds sodium:20, the chemical combination of addition The mol ratio of thing 5 and compound 13 is 17~18:20.
- 6. preparation method according to claim 5, it is characterised in that in step (4), by compound 6 add organic solvent and In water, frozen water is cooled to 0 DEG C, then adds lithium hydroxide stirring reaction 2.5~3.5 hours, and decompression steams organic solvent, then Filtering, filtrate is through extracting, drying, evaporated under reduced pressure obtains compound 7；The compound 6 of addition is 0.5 with the mol ratio of lithium hydroxide ~1.5:3, the volume ratio of organic solvent and water is 1~3:1.
- 7. preparation method according to claim 6, it is characterised in that in step (5), by compound 7,1- hydroxy benzos three Azoles, triethylamine are added in dry methylene chloride, nitrogen protection, are cooled to 0 DEG C, EDCI is added into reaction solution, be warming up to room Temperature stirring, reaction overnight, then by reaction solution evaporated under reduced pressure to solvent-free, frozen water are added into residue, adjusts pH to 3-4, Compound 7A is obtained through extracting, purifying；The compound 7 of addition is 0.8~1.3 with the mol ratio of I-hydroxybenzotriazole:1, add The compound 7 entered and EDCI mol ratio are 0.7~1:1, the mol ratio of compound 7 and triethylamine is 0.2~0.3:1.
- 8. preparation method according to claim 7, it is characterised in that in step (7), be cooled to 4~6 DEG C, the chemical combination of addition The mol ratio of thing 8 and hydrazine hydrate is 0.05~0.2:1.
- 9. preparation method according to claim 8, it is characterised in that in step (8), compound 9 is dissolved in dichloromethane In, then add triethylamine and di-tert-butyl dicarbonate is reacted, evaporated under reduced pressure after the completion of reaction, obtain compound 10；Add The compound 9 entered and the mol ratio of triethylamine are 0.06~0.08:1, the compound 9 of addition and mole of di-tert-butyl dicarbonate Than for 66~68:1.
- 10. preparation method according to claim 9, it is characterised in that in step (10), by 2,4- mesitylenic acids and Dimethylformamide is dissolved in toluene, is cooled to 2-5 DEG C, is warming up to room temperature after adding oxalyl chloride, is stirred overnight, evaporated under reduced pressure obtains To yellow oil, the solution of acid chloride for being dissolved in obtaining dichloromethane in dichloromethane, 2, the 4- mesitylenic acids of addition Mol ratio with oxalyl chloride is 9~11:13；Compound 11, triethylamine are added in dichloromethane, nitrogen protection, are then slowly added to dichloromethane in 0-5 DEG C Solution of acid chloride is reacted, evaporated under reduced pressure after the completion of reaction, and compound 12, the chemical combination of addition are obtained after then scrubbed, filtering The mol ratio of 2,4- mesitylenic acid of the thing 11 with adding is 0.7~0.8:1.
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| US10442770B2 (en) | 2017-02-02 | 2019-10-15 | Assia Chemical Industries Ltd. | Solid state forms of netarsudil mesylate |
| IT201800007398A1 (en) * | 2018-07-20 | 2020-01-20 | PROCESS FOR THE SYNTHESIS OF DIMESILATED NETARSUDIL | |
| CN113121436A (en) * | 2019-12-31 | 2021-07-16 | 江苏艾立康医药科技有限公司 | Preparation method of nertadalal dimethyl sulfonate |
| US11345664B2 (en) | 2019-06-29 | 2022-05-31 | Micro Labs Ltd. | Process for the preparation of (S)-Netarsudil,its salts and polymorphs |
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| US10442770B2 (en) | 2017-02-02 | 2019-10-15 | Assia Chemical Industries Ltd. | Solid state forms of netarsudil mesylate |
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| US11345664B2 (en) | 2019-06-29 | 2022-05-31 | Micro Labs Ltd. | Process for the preparation of (S)-Netarsudil,its salts and polymorphs |
| CN113121436A (en) * | 2019-12-31 | 2021-07-16 | 江苏艾立康医药科技有限公司 | Preparation method of nertadalal dimethyl sulfonate |
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