CN104447445B - A kind of preparation method synthesizing Apremilast intermediate - Google Patents
A kind of preparation method synthesizing Apremilast intermediate Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method synthesizing Apremilast intermediate.The method is to utilize 3-ethyoxyl-4-methoxy-benzoic acid ester and dimethyl sulfone condensation reaction in the basic conditions to generate 2-(3-ethyoxyl-4-methoxybenzene) base-1-mesyl ethyl ketone (II)；This compound ii and Chiral Amine are obtained by reacting 1-N-substituted-amino-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III) in the presence of acidic; gained compound III directly hydrogenates in the presence of a hydrogenation catalyst without separation; obtain product (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine (I); it is Apremilast intermediate, it is possible to make N-acetylamino L-Leu salt further.The preparation method that the present invention also provides for Apremilast.Present invention process flow process is succinct, and safety and environmental protection, cost is low, is beneficial to the industrialized production of cleaning.
Description
Technical field
The present invention relates to the simple and convenient process for preparing of a kind of synthesis Apremilast intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine, belong to medicine bioengineering chemical field.
Background technology
(S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine (I) is the key intermediate preparing Apremilast.Apremilast (Apremilast) is the oral drugs for the treatment of activeness psoriatic arthritis; chemical name is (S)-2-[1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1; 3-diketone, CAS 608141-41-9.This medicine obtains FDA approval in March, 2014 with trade name Otezla (Apremilast), is first oral, selectivity phosphodiesterase 4 (PDE4) inhibitor being also only one and treating for psoriasis in plaques of FDA approval.
US Patent No. 6962940 first reported the synthetic method of Apremilast, two key intermediate condensations obtain, and synthetic route is shown in reaction scheme 1:
The reaction scheme 1 of above-mentioned US6962940 is to adopt the method that first synthesis racemic product splits again, result in the waste of a large amount of (R)-enantiomer, and the intermediate utilization rate of synthesis only has 50%, and total recovery only has 13%.Simultaneously as use the operations such as n-BuLi to require high raw material so that the production of large-scale is restricted.Racemic product splits again, also needs to use a large amount of resolving agent, causes that cost raises, and introduce a large amount of impurity for follow-up synthesis.
Celgene Corp. uses key intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine (I) of following route synthesis Apremilast in US2013217918 and US2014081032:
The method that above-mentioned reaction scheme 2 adopts chirality to synthesize prepares chiral intermediate, but the raw material 3-ethyoxyl-4-methoxy cyanophenyl used is expensive, uses butyl lithium as alkali simultaneously so that large-scale production is restricted；Course of reaction uses substantial amounts of solvent and soda acid, adds the discharge of " three wastes ", is unfavorable for environmental protection.
Reaction scheme 3 and reaction scheme 4, all with 3-ethyoxyl-4-methoxybenzaldehyde for raw material, adopt the method for chirality synthesis to obtain product.But use butyl lithium as alkali, not easily industrial operation, and the method obtains the optical purity of product and only has 80%, does not reach far away product requirement, it is still necessary to purify, and the subsequent product that is introduced as of resolving agent introduces new impurity, and add operating procedure.
Chinese patent CN103864670A discloses the method for synthesis Apremilast, describes following reaction scheme:
Above-mentioned reaction scheme 5 employs dimethyl sulfone list lithium salts when additive reaction, and this list lithium salts is dimethyl sulfone and butyl lithium is prepared in aprotic solvent, inevitably uses the active lithiumation things such as butyl lithium, not easily operates.Meanwhile, use macromole height selectivity Chiral Amine, decrease molecule utilization rate, without industrial value.
Summary of the invention
For the deficiencies in the prior art; the present invention provides a kind of preparation method synthesizing Apremilast intermediate, namely: provide one to prepare the easy technique of (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine (I).
The present invention also provides for a kind of method that (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine (I) utilizing preparation prepares Apremilast further.
Technical scheme is as follows:
The preparation method of (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine shown in a kind of formula (I),
By making 3-ethyoxyl-4-methoxy-benzoic acid ester in solvent orange 2 A; under nitrogen protection and highly basic exist, carry out condensation reaction with dimethyl sulfone, generate the compound shown in formula II: 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone；
Described highly basic is one of solid sodium methylate, solid sodium ethanol, potassium tert-butoxide, sodium hydride or combination；
Described 3-ethyoxyl-4-methoxybenzoic acid ester: highly basic: mol ratio=1:(1～3 of dimethyl sulfone): (1～10)；
Described solvent orange 2 A is one of normal hexane, hexamethylene, toluene, dimethyl sulfoxide, oxolane, 2-methyltetrahydrofuran or combination；
Gained formula II compound is in solvent B; carry out enamine with Chiral Amine in the presence of acidic and be obtained by reacting the compound shown in formula III: 1-N-substituted-amino-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III)
Described solvent B is one of acetic acid, methanol, ethanol, propanol, hexamethylene, oxolane, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene or alkyl halide or combination；Described Chiral Amine is the aromatic amine containing chiral amino, fatty amine containing chiral amino or chiral amino acid；
The not separated directly hydrogenation under hydrogenation catalyst effect of this compound (III), obtains (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine of formula (I).
According to the invention it is preferred to condition is following:
The setting-up point of described 3-ethyoxyl-4-methoxy-benzoic acid ester and dimethyl sulfone is 0-50 DEG C, and the response time is 2-12 hour；It is preferred that 15-35 DEG C, the response time is 5-8 hour.
Described alkene aminating reaction temperature is-30 DEG C to 85 DEG C, it is preferable that-5 DEG C-30 DEG C, the response time is 2-20 hour；
Described hydrogenation temperature is-40 DEG C to 120 DEG C, it is preferable that-15 DEG C to 80 DEG C, it is most preferred that-5 DEG C to 40 DEG C.
According to the invention it is preferred to scheme as follows:
The preparation method of a kind of (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine, comprises the following steps that
(1) under nitrogen protection, in solvent orange 2 A, highly basic is added; in keeping between temperature 15-25 DEG C; dropping dimethyl sulfone, is warming up to 30-35 DEG C, the solvent orange 2 A mixed solution of dropping 3-ethyoxyl-4-methoxy-benzoic acid ester; carry out condensation reaction; react complete, neutralize with ammonium chloride saturated solution, extract; organic facies recycling design, prepares 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II).
(2) under nitrogen protection; in solvent B; add 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II); stir; in keeping between temperature 5 DEG C to 15 DEG C, add acidic catalyst, or also can add appropriate dehydrant; the mixed solution of dropping Chiral Amine and solvent B, described 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II): Chiral Amine mol ratio=1:2 to 1:1 subsequently；
Then 10 DEG C insulation reaction 2-3 hour, obtains the mixed liquor of N-(1-methyl isophthalic acid-phenyl) methyl isophthalic acid-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine；
(3) under nitrogen protection; adding methanol or ethanol in above-mentioned mixed liquor, and add hydrogenation catalyst, nitrogen is replaced 3 times; in keeping between temperature 0 DEG C to 5 DEG C; with hydrogen exchange, after hydrogen exchange, keep Hydrogen Vapor Pressure (reduction pressure) between 0-4.5MPa; subsequently temperature in the kettle is increased to 25 DEG C-35 DEG C; Hydrogen Vapor Pressure strengthens 0.05-0.2MPa again, is incubated hydrogenation reaction, no longer drops to reaction terminating to Hydrogen Vapor Pressure；
After above-mentioned hydrogenation reaction terminates; cooling; nitrogen is replaced; filter, gained solution is concentrated into dry, reclaim methanol or ethanol; residual residue is dissolved in water; dichloromethane extraction, combined dichloromethane phase, it is concentrated into dry (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine shown in product formula (I).
According to the invention it is preferred to, described initiation material 3-ethyoxyl-4-methoxy-benzoic acid ester is 3-ethyoxyl-4-methoxybenzoic acid fatty ester or 3-ethyoxyl-4-methoxybenzoic acid aromatic ester；Wherein: described 3-ethyoxyl-4-methoxybenzoic acid fatty ester, it is preferred to 3-ethyoxyl-4-methoxyl methyl benzoate or 3-ethyoxyl-4-methoxy ethylbenzoate；Described 3-ethyoxyl-4-methoxybenzoic acid aromatic ester is preferably 3-ethyoxyl-4-methoxybenzoic acid benzyl ester.
According to the invention it is preferred to, described solvent orange 2 A is hexamethylene, normal hexane, dimethyl sulfoxide and oxolane, and preferred solvent orange 2 A is one or its mixed solvent of hexamethylene, normal hexane and dimethyl sulfoxide.
According to the invention it is preferred to, described 3-ethyoxyl-4-methoxybenzoic acid ester, highly basic, dimethyl sulfone mol ratio=1:1.5:6 to 1:1:2.
According to the invention it is preferred to, described acidic catalyst is p-methyl benzenesulfonic acid；Or acidic catalyst adds fashionable also with addition of appropriate dehydrant, and dehydrant is selected from titanium tetrachloride or 4A molecular sieve.
According to the invention it is preferred to, described Chiral Amine is chiral benzhydryl base ethamine, chirality o-hydroxy ethamine, chirality naphthalene ethylamine, chirality neighbour's hydroxyl naphthalene ethylamine, chirality phenethylamine or chiral alpha-aminopropanol.
It is further preferred that described Chiral Amine is selected from: one of L-α aminopropanol, S-1-naphthalene ethylamine, S-1-phenethylamine.
According to the invention it is preferred to, described formula II compound: Chiral Amine mol ratio=1:(1.2-1.6).
According to the invention it is preferred to, described hydrogenation catalyst is Pd/C catalyst or Raney's nickel, wherein most preferably carries the Pd/C catalyst of Pd weight 5-10%.
According to the invention it is preferred to, in described hydrogenation reaction, Hydrogen Vapor Pressure controls within the scope of 0-3MPa, is more preferably hydrogenated with under 0.05-0.5MPa low pressure.1-10 hour hydrogenation reaction time, it is preferred that 1-4 hour.
In order to enable long-time storage; ensure that racemization does not occur chiral intermediate; the present invention is it is also preferred that by formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine; react into salt with N-acetamido L-Leu, prepare into (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine N-acetyl group-L-Leu salt.Shown in structure such as following formula (IV):
The preparation method that the present invention also provides for a kind of Apremilast; preparation process (1)-(3) including above-mentioned formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine; it is characterized in that, also continue to following steps:
(4) by making formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine and 3-acetamidophthalic anhydride condensation prepare Apremilast；Or:
Formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine is made to react into salt with 3-acetamidophthalic anhydride with N-acetamido L-Leu, then prepare Apremilast with 3-acetamidophthalic anhydride condensation.
In the preparation method of above-mentioned Apremilast; preferably; formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine and 3-acetamidophthalic anhydride carry out condensation reaction in the presence of catalyst (perchloric acid); reacting 20-40 minute between 75-80 DEG C, then temperature rising reflux reacts 1-2.5 hour；Reaction terminates rear recycling design II, adds ethyl acetate and water, and layering, organic facies dries, concentrates, and residue recrystallisation from isopropanol prepares Apremilast.
In the method for the present invention; the compound ii that initiation material 3-ethyoxyl-4-methoxy-benzoic acid ester and dimethyl sulfone condensation obtain is in a suitable solvent; being obtained by reacting compound III with Chiral Amine enamine in the presence of acidic: 1-N-substituted-amino-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III), not separated directly the hydrogenation under catalyst action of compound III obtains formula (I) intermediate: (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine (I)；It is subsequently used for preparing Apremilast.The reaction related in the present invention, as shown in following reaction scheme 6:
The method is to utilize stable 3-ethyoxyl-4-methoxy-benzoic acid ester as raw material, adopt conventional base catalyst, dimethyl sulfone obtains intermediate compound (II) in alkalescence bar condensation one step, compound (II) and Chiral Amine enamine in the presence of acidic are obtained by reacting 1-N-substituted-amino-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III), compound III is not separated to be directly hydrogenated with under catalyst action, (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine (I) is obtained by the slow cis hydrogenation selectivity under catalysis, Apremilast is prepared in compounds I and 3-acetamidophthalic anhydride condensation；Compound (I) can also react into after salt obtains compound (IV) with N-acetamido L-Leu, then prepares Apremilast with 3-acetamidophthalic anhydride condensation.After chiral intermediate becomes salt, it is not susceptible to racemization, it is simple to store, can guarantee that the optical purity after chiral intermediate long-time storage.
The technical characterstic of the present invention and excellent results:
1, feedstock property of the present invention is stablized inexpensive, reacts simple and easy to control." one kettle way " carries out enamine, enamine reduction and takes off N-aryl-response, decreases using and separating of solvent, and technological process is short, and avoids the harsh reaction conditions such as ultralow temperature, improves process safety, is conducive to operation；Decrease discharge of wastewater simultaneously, economic and environment-friendly.
2, intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine (I) related impurities that the inventive method obtains is few; product purity is high; HPLC purity is up to more than 99.5%; optical purity, up to more than 98.5%, utilizes this intermediate synthesis Apremilast total recovery to may be up to more than 65%.
3, the concise in technology of the present invention, cost is low, route safety and environmental protection, is beneficial to the industrialized production of cleaning, and the synthesis of Apremilast medicine is significant.
Detailed description of the invention
The process monitoring of the reaction of condensation reaction, enamine and reduction reaction utilizes HPLC to detect; final products (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine is to utilize chiral column HPLC to detect purity (area ratio %) calculated yield and e.e. value.
Describe the present invention in detail below in conjunction with embodiment, but the present invention is not only limited to this.
The preparation of embodiment 1:1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II)
Under nitrogen protection; it is sequentially added into 200 grams of normal hexane in 1000 milliliters of dry glass flask; 24 grams (0.6 mole) 60% solid hydride sodium; cooling; in keeping between temperature 15 DEG C to 25 DEG C; drip 188 grams of (2 moles) dimethyl sulfones, within about 2 hours, dropwise, be hereafter warming up to 35 DEG C insulation reaction 1-2 hour (priming reactions).Then in keeping between warm 30 DEG C to 35 DEG C, drip the mixed solution of 126.6 grams of 3-ethyoxyl-4-methoxyl methyl benzoate (0.6 mole) and 200 grams of normal hexane, within about 2 hours, drip and finish, drip and finish 35 DEG C of reactions 4 hours.It is cooled to 20 DEG C; drip 110 grams of saturated aqueous ammonium chlorides; static layering; water layer 100 grams of extraction into ethyl acetate 3 times, organic facies merges, and 30 grams of anhydrous sodium sulfates dry 4 hours; filter; filtrate recycling design obtains off-white color solid 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II) 156.4 gram, yield 95%, HPLC purity 98.3%.
The preparation of embodiment 2:1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II)
Under nitrogen protection, in 1000 milliliters of dry glass flask, it is sequentially added into 200g dimethyl sulfoxide, 200 grams of dimethyl sulfones; 89.6 gram (0.8 mole) potassium tert-butoxide; cooling, keep in temperature 10 DEG C to 20 DEG C between 2 hours, be hereafter warming up to 30 DEG C of insulation reaction 1 to 2 hour.Then in keeping between temperature 33 DEG C to 35 DEG C, add 126.6 grams of 3-ethyoxyl-4-methoxyl methyl benzoate (0.6 mole) in batches, finish 35 DEG C and react 4 hours.It is cooled to 20 DEG C; drip 118 grams of saturated aqueous ammonium chlorides; static layering, water layer 100 grams of extraction into ethyl acetate 3 times, organic facies merges; 30 grams of anhydrous sodium sulfates dry 4 hours; filter, filtrate recycling design, obtain off-white color solid 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II) 147.7 gram; yield 89.7%, HPLC purity 98.9%.
The preparation of embodiment 3:1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II)
Under nitrogen protection; it is sequentially added into 180 grams of hexamethylene in 1000 milliliters of dry glass flask; 36 grams (0.9 mole) 60% solid hydride sodium; cooling; in keeping between temperature 20 DEG C to 25 DEG C; drip 141 grams of (1.5 moles) dimethyl sulfones, within about 2 hours, dropwise, be hereafter warming up to 35 DEG C of insulation reaction 1 to 2 hour.Then keep interior temperature 34-35 DEG C, drip the mixed solution of 134.4 grams of 3-ethyoxyl-4-methoxy ethylbenzoate (0.6 mole) and 200 grams of hexamethylene, within about 2 hours, drip and finish, drip complete 35 DEG C and react 4 hours.It is cooled to 20 DEG C; drip 165 grams of saturated aqueous ammonium chlorides; static layering, water layer 150 grams of extraction into ethyl acetate 3 times, organic facies merges; 30 grams of anhydrous sodium sulfates dry 4 hours; filter, filtrate recycling design, obtain slightly yellow solid 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II) 156.4 gram; yield 84.2%, HPLC purity 96.4%.
Embodiment 4:(S) preparation of-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine (I)
Under nitrogen protection; it is sequentially added into 400 grams of hexamethylene in 1000 milliliters of dry glass flask; 137 grams of (0.5 mole) 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II); cool down after stirring; in keeping between temperature 5 DEG C to 15 DEG C; add 6.0 grams of p-methyl benzenesulfonic acid (0.037 mole) and the solution of 1.9 grams of titanium tetrachlorides (0.01 mole), subsequently 84 grams of S-1-phenethylamines (0.7 mole) of dropping and 200 grams of hexamethylene, within about 2 hours, dropwise.Hereafter 10 DEG C of insulation reaction 2 to 3 hours.The mixed solution obtained, sampling detection, HPLC shows that feed stock conversion is 99.7%, and intermediate N (1-methyl isophthalic acid-phenyl) methyl isophthalic acid-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine, yield is 98%.
Under nitrogen protection, in above-mentioned mixed liquor, add 100 grams of methanol and 5 grams of 10%Pd/C solids, cooling; after nitrogen replaces 3 times; in keeping between temperature 0 DEG C to 5 DEG C, after hydrogen exchange, keep Hydrogen Vapor Pressure between 0.05MPa-0.1MPa; subsequently temperature in the kettle is increased to 25 DEG C-35 DEG C; Hydrogen Vapor Pressure is increased to 0.1-0.3MPa, insulation reaction 1 hour, continue to Hydrogen Vapor Pressure do not decline (sampling; adopt chirality HPLC detection, chirality optical purity > 99%).
After insulation terminates; cooling, nitrogen is replaced, and filters; the mixed liquor obtained is concentrated into dry; residual residue adds 200 grams of water dissolutioies, by 100 grams of dichloromethane extractions 3 times, combined dichloromethane phase; it is concentrated into and dry obtains (S)-1-(3-ethyoxyl-4-methoxyl group) 119.6 grams of phenyl-2-mesyl ethamine; yield 86.34%, purity 99.4%, chirality optical purity 98.7%.
Products therefrom (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine is compound as white solid: fusing point 107.6-108.5 DEG C.
Chirality HPLC: chirality detection post chiralpakAD, 250mm × 4.6mm, column oven temperature 25 DEG C, mobile phase heptane: isopropanol: diethylamine is 55:45:0.1, flow velocity 1ml/min, detection wavelength 240nm, 17.6min (S-type isomer) 99.35%, 24.4min (R-type isomer) 0.65%.
HPLC:AquityUPLCC18,2.1mm × 150mm, mobile phase acetonitrile: 0.1% phosphate aqueous solution, by 10:90 to 90:10, flow: 0.85ml/min, detects wavelength 240nm, column oven temperature 35 DEG C, area normalization method 99.4%.
1HNMR composes (CDCl3, 400MHz): 1.44 (t, J=7.0HZ, 3H), 1.87 (bs, 2H), 2.88 (s, 3H), 3.20 (dd, J1,2=3.0Hz, J1,3=14.0Hz, 1H), 3.30 (dd, J1,2=9.5Hz, J1,3=14.0Hz, 1H), 3.83 (s, 3H), 4.08 (q, J7.0Hz, 2H), 4.55 (dd, J1,2=3.0Hz, J1,3=9.5Hz, 1H), 6.90 (m, 3H).
Embodiment 5:(S) preparation of-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine (I)
Under nitrogen protection; it is sequentially added into 300 grams of methanol in 1000 milliliters of dry glass flask; 137 grams of (0.5 mole) 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II); cool down after stirring; add 6.0 grams of p-methyl benzenesulfonic acid (0.037 mole) and 4A molecular sieve; in keeping between temperature 5 DEG C to 15 DEG C; the solution of 52.5 grams of L-α aminopropanols (0.7 mole) of dropping and 60 grams of methanol, dropwises for about 2 hours subsequently.Hereafter 10 DEG C of insulation reaction 2 to 3 hours.The mixed solution obtained, sampling detection, HPLC shows that feed stock conversion is 97.1%, and intermediate N (1-methyl isophthalic acid-methylol) methyl isophthalic acid-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine yield is 96.7%.
Under nitrogen protection; the mixing liquid of 50 grams of methanol and 5 grams of 10%Pd/C solids is added in above-mentioned mixed liquor; cooling; after nitrogen replaces 3 times; in keeping between negative 5 DEG C to 5 DEG C of temperature; after hydrogen exchange; keep Hydrogen Vapor Pressure between 0.05MPa-0.12MPa; subsequently temperature in the kettle is increased to 30 DEG C-35 DEG C; Hydrogen Vapor Pressure is increased to 0.2-0.38MPa, insulation reaction 3 hours, continue to Hydrogen Vapor Pressure do not decline (sampling; adopt chirality HPLC detection, chirality optical purity > 99%).After insulation terminates; cooling, nitrogen is replaced, and filters; the mixed liquor obtained is concentrated into dry; residual residue adds 200 grams of water dissolutioies, by 100 grams of dichloromethane extractions 3 times, combined dichloromethane phase; it is concentrated into and dry obtains (S)-1-(3-ethyoxyl-4-methoxyl group) 126 grams of phenyl-2-mesyl ethamine; yield 90.9%, purity 99.5%, chirality optical purity 99.4%.Embodiment 6:(S) preparation of-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine (I)
Under nitrogen protection; it is sequentially added into 300 grams of ethanol in 1000 milliliters of dry glass flask; 137 grams of (0.5 mole) 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II); cool down after stirring; add 6.0 grams of p-methyl benzenesulfonic acid (0.037 mole); in keeping between temperature 5 DEG C to 15 DEG C, the solution of 150 grams of S-1-naphthalene ethylamines (0.7 mole) of dropping and 100 grams of methanol, dropwises for about 3 hours subsequently.Hereafter 10 DEG C of insulation reaction 2 to 3 hours.The mixed solution obtained, sampling detection, HPLC shows that feed stock conversion is 99.5%, and intermediate N (1-methyl isophthalic acid-naphthyl) methyl isophthalic acid-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine yield is 97.7%.
Under nitrogen protection; adding the mixing liquid of 50 grams of ethanol and 5 grams of 10%Pd/C solids in above-mentioned mixed liquor, cooling, after nitrogen replaces 3 times; in keeping between temperature 5 DEG C to 15 DEG C; after hydrogen exchange, keep Hydrogen Vapor Pressure between 0.05MPa-0.09MPa, subsequently temperature in the kettle is increased to 30 DEG C-35 DEG C; Hydrogen Vapor Pressure is increased to 0.1-0.26MPa; insulation reaction 2.5 hours (sampling adopts chirality HPLC detection, chirality optical purity > 99%).After insulation terminates; cooling, nitrogen is replaced, and filters; the mixed liquor obtained is concentrated into dry; residual residue adds 200 grams of water dissolutioies, by 100 grams of dichloromethane extractions 3 times, combined dichloromethane phase; it is concentrated into and dry obtains (S)-1-(3-ethyoxyl-4-methoxyl group) 128.8 grams of phenyl-2-mesyl ethamine; yield 93%, purity 99.1%, chirality optical purity 99.6%.
Embodiment 7:(S) preparation of-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine N-acetyl group-L-Leu salt
Under nitrogen protection, to equipped with mechanical agitation, dry 1000 milliliters of glass flask of thermometer and condensing tube add (S)-1-(3-ethyoxyl-4-methoxyl group) 110 grams of-2-mesyl ethamine of phenyl (0.4mol), N-acetyl group leucine 69.3 grams (0.4mol) and methanol 500 grams, the lower heating of stirring is to refluxing 1 hour, then under stirring, it is cooled to ambient temperature, and at room temperature stir 3 hours, filter, and use methanol washing leaching cake, subsequently under vacuo dry cake to constant weight, obtain 176.3 grams of (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine N-acetyl group-L-Leu salt (optical purity 99.6%) yield 98.3%.
Chirality HPLC (ethanol: 20mMKH2PO4=1:99, PH=7.0, the ES-OVM chiral chromatographic column of Agilent company, 150mm × 4.6mm, flow velocity is 0.5ml/min, and detection wavelength is 240nm): 18.1min (S type isomer, 99.6%), 25.0min (R type isomer, 0.4%)
The preparation of embodiment 8:S-2-[1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-diketone (Apremilast)
nullUnder nitrogen protection，(S)-1-(3-ethyoxyl-4-methoxyl group) 60.0 grams (0.22 mole of phenyl-2-mesyl ethamine it is sequentially added in 1000 milliliters of dry glass flask，99.4%e.e.)，3-acetamidophthalic anhydride (49.0 grams，0.23mol) with 500 grams of glacial acetic acid，After stirring，3 grams of perchloric acid is dripped in 30 minutes，Reaction 30 minutes between temperature 65 DEG C to 85 DEG C in keeping，Temperature rising reflux 2 hours subsequently，Remove recovery glacial acetic acid subsequently under reduced pressure，Then leftover materials are cooled to room temperature，It is separately added into 200 grams of saturated aqueous common salts and 300 grams of acetic acid ethyl dissolutions，Stirring layering，Divide and take organic facies，Evaporated under reduced pressure，Residue obtains 82.8 grams of solids (yield 80%) after recrystallisation from isopropanol，For Apremilast (S-2-[1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-diketone)，Optical purity 99.1%，Purity 99.5%.
Claims (12)
1. (S)-1-(3-ethyoxyl-4-methoxyl group shown in formula (I)) preparation method of phenyl-2-mesyl ethamine,
By making 3-ethyoxyl-4-methoxy-benzoic acid ester in solvent orange 2 A, under nitrogen protection and highly basic exist, carry out condensation reaction with dimethyl sulfone, generate the compound shown in formula II: 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone；
Described highly basic is one of solid sodium methylate, solid sodium ethanol, potassium tert-butoxide, sodium hydride or combination；
Described 3-ethyoxyl-4-methoxybenzoic acid ester: highly basic: mol ratio=1:(1 ~ 3 of dimethyl sulfone): (1 ~ 10)；
Described solvent orange 2 A is one of normal hexane, hexamethylene, toluene, dimethyl sulfoxide, oxolane, 2-methyltetrahydrofuran or combination；
Gained formula II compound, in solvent B, carries out enamine in the presence of acidic and is obtained by reacting the compound shown in formula III with Chiral Amine: 1-N-substituted-amino-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III),
Described solvent B is one of acetic acid, methanol, ethanol, propanol, hexamethylene, oxolane, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene or alkyl halide or combination；Described Chiral Amine is the aromatic amine containing chiral amino, fatty amine containing chiral amino or chiral amino acid；
The not separated directly hydrogenation under hydrogenation catalyst effect of this compound (III), obtains (S)-1-(3-ethyoxyl-4-methoxyl group of formula (I)) phenyl-2-mesyl ethamine.
2. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, comprise the following steps that
(1) under nitrogen protection, in solvent orange 2 A, highly basic is added; in keeping between temperature 15-25 DEG C; dropping dimethyl sulfone, is warming up to 30-35 DEG C, the solvent orange 2 A mixed solution of dropping 3-ethyoxyl-4-methoxy-benzoic acid ester; carry out condensation reaction; react complete, neutralize with ammonium chloride saturated solution, extract; organic facies recycling design, prepares 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II)；
(2) under nitrogen protection; in solvent B; add 1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethyl ketone (II); stir; in keeping between temperature 5 DEG C to 15 DEG C, add acidic catalyst, or also can add appropriate dehydrant; the mixed solution of dropping Chiral Amine and solvent B, described 1-(3-ethyoxyl-4-methoxyl group subsequently) phenyl-2-mesyl ethyl ketone (II): Chiral Amine mol ratio=1:2 to 1:1；
Then 10 DEG C insulation reaction 2-3 hour, obtains N-(1-methyl isophthalic acid-phenyl) mixed liquor of methyl isophthalic acid-(3-ethyoxyl-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine；
(3) under nitrogen protection; adding methanol or ethanol in above-mentioned mixed liquor, and add hydrogenation catalyst, nitrogen is replaced 3 times; in keeping between temperature 0 DEG C to 5 DEG C; with hydrogen exchange, after hydrogen exchange, keep Hydrogen Vapor Pressure between 0-4.5MPa; subsequently temperature in the kettle is increased to 25 DEG C-35 DEG C; Hydrogen Vapor Pressure strengthens 0.05-0.2MPa again, is incubated hydrogenation reaction, no longer drops to reaction terminating to Hydrogen Vapor Pressure；
After above-mentioned hydrogenation reaction terminates; cooling; nitrogen is replaced; filter, gained solution is concentrated into dry, reclaim methanol or ethanol; residual residue is dissolved in water; dichloromethane extraction, combined dichloromethane phase, it is concentrated into dry (the S)-1-(3-ethyoxyl-4-methoxyl group shown in product formula (I)) phenyl-2-mesyl ethamine.
3. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described initiation material 3-ethyoxyl-4-methoxy-benzoic acid ester is 3-ethyoxyl-4-methoxybenzoic acid fatty ester or 3-ethyoxyl-4-methoxybenzoic acid aromatic ester.
4. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described 3-ethyoxyl-4-methoxybenzoic acid ester, highly basic, dimethyl sulfone mol ratio=1:1.5:6 to 1:1:2.
5. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described acidic catalyst is p-methyl benzenesulfonic acid.
6. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described Chiral Amine is chiral benzhydryl base ethamine, chirality o-hydroxy ethamine, chirality naphthalene ethylamine, chirality neighbour's hydroxyl naphthalene ethylamine, chirality phenethylamine or chiral alpha-aminopropanol.
7. (the S)-1-(3-ethyoxyl-4-methoxyl group as described in claim 1 or 6) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described Chiral Amine is selected from: one of L-α aminopropanol, S-1-naphthalene ethylamine, S-1-phenethylamine.
8. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described formula II compound: Chiral Amine mol ratio=1:(1.2-1.6).
9. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described hydrogenation catalyst is Pd/C catalyst or Raney's nickel.
10. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that described hydrogenation catalyst is the Pd/C catalyst of load Pd5-10% weight ratio.
11. (S)-1-(3-ethyoxyl-4-methoxyl group as claimed in claim 1) preparation method of phenyl-2-mesyl ethamine; it is characterized in that formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine; react into salt with N-acetamido L-Leu, prepare into (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine N-acetyl group-L-Leu salt.
12. a preparation method for Apremilast, formula (I) intermediate (the S)-1-(3-ethyoxyl-4-methoxyl group including described in claim 1) preparation method of phenyl-2-mesyl ethamine, it is characterised in that also continue to following steps:
By making formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine and 3-acetamidophthalic anhydride condensation prepare Apremilast；Or:
Making formula (I) intermediate (S)-1-(3-ethyoxyl-4-methoxyl group) phenyl-2-mesyl ethamine reacts into salt with N-acetamido L-Leu, then prepares Apremilast with 3-acetamidophthalic anhydride condensation.
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| CN104892486B (en) * | 2015-06-25 | 2017-12-08 | 济南纽华医药科技有限公司 | The crystal formation B of Apremilast+And preparation method thereof |
| US9765026B2 (en) | 2015-08-28 | 2017-09-19 | Scinopharm Taiwan, Ltd. | Forms of apremilast and the process of making the same |
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| WO2017094031A2 (en) * | 2015-12-04 | 2017-06-08 | Sun Pharmaceutical Industries Limited | Novel process for preparation of apremilast |
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| CN108084066A (en) * | 2017-12-12 | 2018-05-29 | 中山大学 | A kind of synthetic method of Apremilast and enantiomter |
| CN108752248A (en) * | 2018-07-17 | 2018-11-06 | 常州大学 | A method of synthesis 1- (3- ethyoxyl -4- methoxyl groups) phenyl -2- mesyl ethamine |
| CN111943875B (en) * | 2020-01-06 | 2021-06-29 | 东莞市东阳光仿制药研发有限公司 | Preparation method of PDE-4 inhibitor intermediate |
| CN112694426B (en) * | 2020-12-29 | 2022-11-04 | 山东铂源药业股份有限公司 | Synthetic method of apremilast intermediate |
| CN115894310A (en) * | 2021-08-13 | 2023-04-04 | 江苏正大清江制药有限公司 | Novel preparation method of apremilast chiral amine intermediate |
| CN115850129B (en) * | 2023-02-28 | 2023-05-16 | 凯莱英生命科学技术(天津)有限公司 | Process for the preparation of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine |
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Denomination of invention: A Preparation Method for Synthesizing the Intermediate of Apste Effective date of registration: 20221213 Granted publication date: 20160706 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |