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CN108727291A - The preparation method of Ao Zhamode and its intermediate - Google Patents

The preparation method of Ao Zhamode and its intermediate Download PDF

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Publication number
CN108727291A
CN108727291A CN201710267498.1A CN201710267498A CN108727291A CN 108727291 A CN108727291 A CN 108727291A CN 201710267498 A CN201710267498 A CN 201710267498A CN 108727291 A CN108727291 A CN 108727291A
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Prior art keywords
compound
zhamode
iii
protecting group
preparation
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张席妮
周涛
熊志刚
钟健
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Ningbo Ainuo Medical Technology Co Ltd
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Ningbo Ainuo Medical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • 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
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides the preparation methods of Ao Zhamode and its intermediate.The method of the present invention is to pass through suitable method prepare compound III with 2,3- dihydro -4- cyano -1- indones for raw material.The amido and hydroxyl of compound III are protected using protective agent, compound IV is made.Compound IV is subjected to salt treatment and obtains compound V.Compound V and compound VI are subjected to ring-closure reaction, compound VII is made.Compound VII is carried out to be deprotected obtained Ao Zhamode.The method of the present invention reduces reaction step compared with conventional method, improves total recovery, and it is high to prepare product quality；Reaction condition is mild, avoids the application of dangerous operating conditions, poisonous reagent and expensive chemical reagent, not only solves safety issue present in conventional method, and reduce cost, is suitble to industrialized production.

Description

The preparation method of Ao Zhamode and its intermediate
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to the preparation method of Ao Zhamode and its intermediate.
Background technology
Ao Zhamode (chemical names：5- [3- [(1S) -2,3- dihydros -1- [(2- ethoxys) amido] -1H- indenes -4- Base] -1,2,4- E diazole -5- bases] -2- (1- methyl ethoxies)-benzonitrile), English name：Ozanimod.It is mainly used for multiple The treatment of property sclerosis, ulcerative colitis and Crohn disease.Wherein, multiple sclerosis and the ulcerative colitis not only course of disease Long, incidence height, and need medication all the year round.As it can be seen that Ao Zhamode market capacitys are huge, foreground is considerable.
The patent CN201080061144.8 of Rui Saiputuosi companies of the U.S. is disclosed with (R)-(+) -2- methyl-2-propyls Sulfenamide is raw material with 4- cyano -1- indones, and imines is obtained by condensation reaction, and the chiral of sulfonamide is then recycled to carry out Induction Control, the chiral amino protected after sodium borohydride reduction, hydrolyzes sulfinyl, obtains Chiral Amine under strongly acidic conditions The method of base.Reaction route is as follows：
This method has the following disadvantages：
(1) reaction route is long, there is the reaction of 9 steps, and that there are life cycle of the product is long, total recovery is low and what production cost was high lacks Point, a mole total recovery are only 31%；
(2) it needs to use poisonous reagent zinc cyanide in first step reaction, harm to the human body is big, and labour protection requires high, behaviour It is inconvenient to make；
(3) reaction condition of second step requires anhydrous and oxygen-free, and height is required to operation, inconvenient for operation；
(4) the 6th steps use NaH and DMF, and reaction safety is poor, easily explode；Product quality made from this method is low, Chiral purity (ee%) is only 95%；
(5) expensive reagent (R)-(+) -2- methyl-2-propyl sulfenamides in addition are used in reaction, greatly improved Production cost.
Invention content
It is an object of the invention to solve problem above, provide that a kind of production cost is low, safety is good, is suitble to industrial metaplasia The Ao Zhamode of production and its preparation method of intermediate.
Realizing the technical solution of above-mentioned purpose of the present invention is：The preparation method of Ao Zhamode and its intermediate, it be with 2, 3- dihydro -4- cyano -1- indones are raw material, and compound III is made by suitable method.Use protective agent to compound thereafter The amido and hydroxyl of III is protected, and midbody compound IV is obtained；Thereafter by compound IV and azanol or the relevant salt of azanol Midbody compound V is made in reaction；Thereafter, in the presence of suitable solvent and alkali, compound V and compound VI are subjected to ring It closes reaction and obtains midbody compound VII；Finally, the protecting group that compound VII is sloughed with deprotection method appropriate, obtains Ao Zhamode.Specific reaction step is as follows：
A) it with 2,3- dihydro -4- cyano -1- indones (compound as shown in II) for raw material, under suitable condition, closes
At compound III.
B) compound IV is prepared by protection to the amido and hydroxyl of compound III using protective agent.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
C) compound V is made from azanol or the relevant salt treatment compound IV of azanol.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
D) compound VII is occurred obtained from condensation reaction by compound V and compound VI.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
E) compound I Ao Zhamode are prepared by sloughing the protecting group of Formula VII compound with deprotection method.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
Above-mentioned step a) -1：Using compound II as raw material, in the presence of a catalyst, through asymmetric reduction reaction preparationization Close object III.
Above-mentioned step a) -2：Using compound II as raw material, it is condensed with ethylaminoethanol, under appropriate solvent, uses reducing agent Restored to obtain the raceme formula III-A of compound III, compound III-A is split under the conditions of chiral acid, changed Close object III.
Above-mentioned step a) -1, using compound II as raw material, in the presence of a catalyst, through asymmetric reduction reaction preparationization Object III is closed, the catalyst is selected from least one of metallic catalyst, chiral phosphoric acid catalyst or chiral sulfonic acid catalyst, Wherein metallic catalyst, which is selected from, contains Ru, Ni, Cu, the metallic catalyst of Pt or Co metals；Above-mentioned step a) -2, with chemical combination Object II is raw material, it carries out reduction reaction with reducing agent and obtains the raceme formula III-A of compound III, compound III-A is in hand Property acid under the conditions of split, obtain compound III.The reducing agent of above-mentioned reduction reaction is boron hydride, tetrahydrochysene lithium aluminium, hydrogen At least one of gas, formic acid or formates；The chiral resolving agent of above-mentioned chiral resolution reaction method is D- mandelic acids, D- winestones At least one of acid, D- camphoric acids, D- camphorsulfonic acids, D-ALPHA-Hydroxypropionic acid, D-malic acid, diacetone-L- 2-KLGs, D-Glu；
The compound as shown in formula IV；
Wherein, R1For H or hydroxyl protection base；R2For H or amido protecting group.
Compound shown as a formula V.
Wherein, R1For H or hydroxyl protection base；R2For H or amido protecting group.
The compound as shown in Formula VII.
Wherein, R1For H or hydroxyl protection base；R2For H or amido protecting group.
The positive effect of the present invention is：
(1) present invention reduces the synthesis step of Ozanimod, only 5-6 step reactions not only shorten the production of product Period, and improve mole total recovery and quality of product.
(2) inventive process avoids NaH, DMF composite reagent of safety difference and expensive reagent (R)-(+)- The application of 2- methyl-2-propyl sulfenamides, but cheap greenization supplementary material is used, not only increase the peace of reflection Quan Xing, and reduce the cost of reaction.
(3) reaction condition of the present invention is mild, avoids the operating procedure of anhydrous and oxygen-free, easy to operate, it is easy to accomplish.
(4) highway route design of the invention is novel, and 5 reaction intermediates of gained are novel compounds, production process environment Close friend, securely and reliably, total recovery are high, at low cost, are suitble to industrialized production.
Specific implementation mode
Following embodiment is illustrative, is not intended to limitation claimed invention range.
Embodiment 1
Under nitrogen protection, dichloromethane (400 is added into the three-necked bottle comprising compound II (15.7 grams, 0.1 mole) Milliliter), sequentially add metallic catalyst (0.80 gram, 0.001 mole) containing Ru, iodine (0.127 gram, 0.001 mole), (S, S bis- [4, the 5- dihydroxy -3H- biphenyl phosphorus] benzene (0.80 gram, 0.001 mole) of)-f-1,2-, hydrogenated at normal pressure 24 is small at 20 DEG C When, solution washs organic layer with saturated aqueous sodium sulfite, saturated sodium-chloride water solution successively after diatomite filters, warp After anhydrous sodium sulfate drying, filtering and concentrating obtains 18.0 grams of white solid, purity 99%, yield 90%.
1HNMR (400MHz, DMSO) δ 7.50-7.31 (m, 3H), 4.04 (m, 1H), 3.62 (q, 2H, J=5.5Hz), 3.57-3.43(m,1H),3.27(ddd,1H ,J1=17.6Hz, J2=9.1Hz, J3=5.0Hz), 3.15-2.85 (m, 1H), 2.74(m,2H),2.58(dtd,1H,J1=9.0 Hz, J2=5.5Hz, J3=5.3Hz, J4=3.6Hz), 2.20 (ddd, 1H, J1 =13.4Hz, J2=8.9Hz, J3=4.6Hz)
Embodiment 1A- embodiments 1B
The preparation method of embodiment 1A- embodiments 1B is substantially the same manner as Example 1, the difference is that catalyst is different, Specifically it is shown in Table 1.
Table 1
Catalyst Molar yield
Embodiment 1 Metallic catalyst containing Ru 90%
Embodiment 1A Metallic catalyst containing Co 86%
Embodiment 1B Chiral phosphoric acid catalyst 84%
Embodiment 1C Chiral sulfonic acid catalyst 73%
Embodiment 2
(1) reduction reaction
Under nitrogen protection, tetrahydrofuran is added into the three-necked bottle of the compound (15.7 grams, 0.1 mole) comprising Formula II (400 milliliters), and reactant is cooled to -78 DEG C, sodium borohydride (3.4 grams, 0.1 mole) is added portionwise in 30 minutes. It is reacted 30 minutes at -78 DEG C, 0 DEG C is then warming up in 1 hour.It is quenched instead with saturated sodium-chloride water solution (100 milliliters) It answers, saturation aqueous sodium potassium tartrate (420 milliliters) is added, reaction is quenched, it is mixed with ethyl acetate (1500 milliliters) diluting reaction Object, liquid separation are closed, organic layer is washed with saturated ammonium chloride, water and saturated sodium-chloride successively.Organic layer is dried with magnesium sulfate, filtering, Filtrate is concentrated, 13.6 grams of brown oil is obtained, is directly used in without purifying and reacts in next step.
(2) chiral resolution
Under nitrogen protection, the compound of formula III-A (20.2 grams, 0.1 mole) is dissolved in isopropanol (100 milliliters) In, slowly (19.4 grams are dissolved in 50 milliliters of isopropanols the aqueous isopropanol of dropwise addition D- acetyl mandelic acids, and 0.1 rubs at room temperature You), after stirring 1 hour, filtering, filter cake is recrystallized with butanone/normal heptane, obtains white solid, the i.e. mandelic acid of compound III Salt.The white solid of gained is dissolved in purified water (100 milliliters), pH to 9-10 is neutralized to unsaturated carbonate aqueous solutions of potassium, White solid, filtering is precipitated, filter cake water wash depressurizes lower drying, obtains 7.2 grams of the compound of formula III, and purity 99% is received Rate 35%.
1HNMR (400MHz, DMSO) δ 7.50-7.31 (m, 3H), 4.04 (m, 1H), 3.62 (q, 2H, J=5.5Hz), 3.57-3.43(m,1H),3.27(ddd,1H ,J1=17.6Hz, J2=9.1Hz, J3=5.0Hz), 3.15-2.85 (m, 1H), 2.74(m,2H),2.58(dtd,1H,J1=9.0 Hz, J2=5.5Hz, J3=5.3Hz, J4=3.6Hz), 2.20 (ddd, 1H, J1 =13.4Hz, J2=8.9Hz, J3=4.6Hz)
Embodiment 2A- embodiments 2C
Embodiment 2A- embodiment 2C preparation methods steps (1) and (1) the step of embodiment 2 are essentially identical, difference
It is in reducing agent difference, is specifically shown in Table 2.Embodiment 2A- embodiment 2C preparation methods steps (2) and embodiment
2 the step of (2), is identical.
Table 2
Reducing agent Molar yield
Embodiment 2 Sodium borohydride 35%
Embodiment 2A Tetrahydrochysene lithium aluminium 38%
Embodiment 2B Acetic acid 41%
Embodiment 2C Hydrogen 26%
Embodiment 2D- embodiments 2H
The step of embodiment 2D- embodiment 2H preparation methods (1), is identical as (1) the step of embodiment 2, and embodiment 2D- is real The step of applying 2H preparation methods (2) and (2) the step of embodiment 2 is essentially identical, the difference is that resolving agent is different, specifically It is shown in Table 3.
Table 3
Embodiment 3
Under nitrogen protection, the compound of formula III (20.2 grams, 0.1 mole) is dissolved in acetone (100 milliliters), (10.2 grams, 0.12 rubs for addition para-methylbenzenepyridinsulfonate sulfonate (2.85 grams, 0.01 mole) and 2,2-dimethoxypropane at room temperature You), it after stirring 3 hours, is filtered by silicagel pad, filters off pigment, obtain colourless solution, white solid is concentrated to give under decompression, done It is dry, obtain 23.4 grams of the compound of formula IV -1, purity 99%, yield 96.7%.
1HNMR (400MHz, DMSO) δ 7.50-7.31 (m, 3H), 4.08 (m, 1H, J=6.1Hz), 3.62 (q, 2H, J= 5.5Hz),3.57-3.43(m,1H),3.2 7(ddd,1H,J1=17.6Hz, J2=9.1Hz, J3=5.0Hz), 3.15-2.85 (m, 1H, J=24.2Hz), 2.58 (dtd, 1H, J1=9.0Hz, J2=5.5Hz, J3=5.3Hz, J4=3.6Hz), 2.48 (ddd,1H,J1=13.4Hz, J2=8.9Hz, J3=4.6Hz), 1.30 (s, 6H)
Embodiment 3A embodiments 3B
Embodiment 3A preparation methods are substantially the same manner as Example 3, the difference is that protective agent is different, are specifically shown in Table 4.
Table 4
Protective agent Molar yield
Embodiment 3 2,2- dimethoxy propanes 96.7%
Embodiment 3A Chlorotriethyl silane 95.3%
Embodiment 4
Under nitrogen protection, add into ethyl alcohol (200 milliliters) solution of the compound of formula IV -1 (24.2 grams, 0.1 mole) Enter hydroxylamine hydrochloride (21.0 grams, 0.3 mole) and triethylamine (30.3 grams, 0.3 mole).Reaction mixture refluxed 4 is small at 80 DEG C When.Reaction mixture is cooled to room temperature, and is concentrated to dryness, (500 milliliters) dilutions of dichloromethane are then used.With sodium bicarbonate, Water and salt water washing organic layer.It is dried over magnesium sulfate to merge organic layer, and concentrates to generate 28.3 grams of white foam solids, i.e., The compound of Formula V -1 can be directly used for reacting in next step without further purification.
Embodiment 5
Under nitrogen protection, to the n,N-Dimethylformamide of the compound of Formula V -1 (27.5 grams, 0.1 mole) (110 millis Rise) carboxylic acid VI (20.5 grams, 0.1 mole), carbodiimides (23.0 grams, 0.12 mole) and 1- hydroxy benzos are added in solution Triazole (16.2 grams, 0.12 mole).It reacts at room temperature 2 hours, reaction mixture is then heated to 80 DEG C, reaction 12 is small When.Reaction mixture is cooled to room temperature, (250 milliliters) dilutions of ethyl acetate are used in combination.Use NaHCO3, water and salt water washing it is organic Layer.Merge organic layer through MgSO4It is dry, and concentrate to generate 46.0 grams of white foam solids, the i.e. compound of Formula IV -1, no It is purified to can be directly used for reacting in next step.
1HNMR (400MHz, DMSO) δ 8.53 (d, 1H, J=2.3Hz), 8.42 (dd, 1H, J1=7.6Hz, J2= 2.3Hz), 8.17 (d, 1H, J=7.7Hz), 7.97 (d, 1H, J=7.6Hz), 7.63-7 .50 (m, 2H), 5.28 (t, 1H, J= 5.0Hz), 4.99 (m, 1H, J=6.1Hz), 4.92 (s, 1H), 3.62 (q, 2H, J=5. 5Hz), 3.57-3.43 (m, 1H), 3.27(ddd,1H, J1=17.6Hz, J2=9.1Hz, J3=5.0Hz), 3.15-2.85 (m, 2H, J=24.2Hz), 2.58 (dtd,1H,J1=9.0Hz, J2=5.5Hz, J3=5.3Hz, J4=3.6Hz), 2.48 (ddd, 1H, J1=13.4Hz, J2= 8.9Hz,J3=4.6Hz), 1.39 (d, 6H, J=6.0Hz), 1.30 (s, 6H)
Embodiment 6
Under nitrogen protection, molten to the methanol solution (110 milliliters) of the compound of Formula VII -1 (44.4 grams, 0.1 mole) Concentrated hydrochloric acid (5 milliliters, 0.06 mole) is added in liquid, reacts 2 hours at room temperature, white solid is precipitated, lower drying is depressurized in filtering That is the compound of Formulas I, 26.8 grams of white solid, purity 99%, yield 66.3%.
1HNMR (400MHz, DMSO) δ 9.25 (s, 2H), 8.53 (d, 1H, J=2.3Hz), 8.42 (dd, 1H, J1= 7.6Hz,J2=2.3Hz), 8.17 (d, 1H, J=7.7Hz), 7.97 (d, 1H, J=7.6Hz), 7.63-7 .50 (m, 2H), 5.28 (t, 1H, J=5.0Hz), 4.99 (m, 1H, J=6.1Hz), 4.92 (s, 1H), 3.72 (q, 2H, J=5. 5Hz), 3.57- 3.43(m,1H),3.27(ddd,1H, J1=17.6Hz, J2=9.1Hz, J3=5.0Hz), 3.15-2.85 (m, 2H, J= 24.2Hz),2.53(dtd,1H,J1=9.0Hz, J2=5.5Hz, J3=5.3Hz, J4=3.6Hz), 2.30 (ddd, 1H, J1= 13.4Hz,J2=8.9Hz, J3=4.6Hz), 1.39 (d, 6H, J=6.0Hz).

Claims (9)

1. the preparation method of Ao Zhamode and its intermediate, this approach includes the following steps：With 2,3- dihydro -4- cyano -1- indenes Ketone is raw material, and compound III is made through suitable method.The amido and hydroxyl of compound III are protected using protective agent, Compound IV is made.Compound IV is subjected to salt treatment and obtains compound V.Compound V and compound VI are subjected to ring-closure reaction system Obtain compound VII.Compound VII is carried out to be deprotected obtained Ao Zhamode.
A) with 2,3- dihydro -4- cyano -1- indones (compound as shown in II) for raw material, under suitable condition, chemical combination is synthesized Object III.
B) compound IV is prepared by protection to the amido and hydroxyl of compound III using protective agent.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
C) compound V is made from azanol or the relevant salt treatment compound IV of azanol.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
D) compound VII is occurred obtained from condensation reaction by compound V and compound VI.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
E) compound I Ao Zhamode are prepared by sloughing the protecting group of Formula VII compound with deprotection method.
Wherein, R1For hydroxyl protection base, R2For amido protecting group.
2. the preparation method of Ao Zhamode according to claim 1, which is characterized in that the step a) is with compound II is raw material, in the presence of a catalyst, through asymmetric reduction reaction prepare compound III.
。
3. the preparation method of Ao Zhamode according to claim 1, which is characterized in that the step a) is with compound II is raw material, is condensed with ethylaminoethanol, under appropriate solvent, is restored to obtain the raceme formula of compound III with reducing agent III-A, compound III-A are split under the conditions of chiral acid, obtain compound III.
。
4. the preparation method of Ao Zhamode intermediate compound IIIs according to claim 2, which is characterized in that described Catalyst is selected from least one of metallic catalyst, chiral phosphoric acid catalyst or chiral sulfonic acid catalyst.Wherein metallic catalyst Selected from containing Ru, Ni, Cu, the metallic catalyst of Pt or Co metals.
5. the preparation method of Ao Zhamode according to claim 3, which is characterized in that the reducing agent is hydroboration At least one of object, tetrahydrochysene lithium aluminium, hydrogen, formic acid or formates.
6. the preparation method of Ao Zhamode according to claim 1, which is characterized in that the chiral resolving agent is that D- is flat In peach acid, D- tartaric acid, D- camphoric acids, D- camphorsulfonic acids, D-ALPHA-Hydroxypropionic acid, D-malic acid, diacetone-L- 2-KLGs, D-Glu At least one.
7. the compound as shown in formula IV.
Wherein, R1For H or hydroxyl protection base；R2For H or amido protecting group.
8. compound shown as a formula V.
Wherein, R1For H or hydroxyl protection base；R2For H or amido protecting group.
9. the compound as shown in Formula VII.
Wherein, R1For H or hydroxyl protection base；R2For H or amido protecting group.
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WO2021009306A1 (en) * 2019-07-16 2021-01-21 Synthon B.V. Improved process for preparing ozanimod

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Application publication date: 20181102