CN105348276A - Synthetic method for 1-{2-floro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid - Google Patents
Synthetic method for 1-{2-floro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidinecarboxylic acid Download PDFInfo
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Abstract
The invention provides a synthetic method for a compound 1-{2-floro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid represented by a formula 2. The synthetic method is simple in reaction condition, simple and convenient in post-treatment, easy to operate, high in yield, stable in process and suitable for industrial production.
Description
Technical field
The application belongs to technical field of medicine synthesis, is specifically related to the fluoro-4-of immunomodulatory compounds 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } synthetic method of-3-azetidinecarboxylic acid.
Background technology
Known in this field, lymphocyte needs the existence of sphingosine-1-phosphate one receptoroid (S1P1) derive from Lymphoid tissue and enter peripheral circulation, and S1P1 internalization can stop lymphocyte derive from Lymphoid tissue and be limited to Lymphoid tissue by these important immunocytes.
Large quantity research shows, there is multiple S1P1 receptor stimulant, and they can be attached to homoreceptor that lymphocyte is expressed and cause S1P1 receptor internalisation, then stops lymphocyte to be derived.So S1P1 receptor stimulant starts immunoreactive ability by stoping lymphocytic transport to reduce human body, thus can be used for the treatment of various autoimmune disorder as immunosuppressor.
Many S1P1 receptor stimulants were described, and wherein most typical compound is FTY720 (having another name called " FTY720 ").Current Novartis Co., Ltd just with the trade(brand)name sales promotion FTY720 of Gilenya, for treatment multiple sclerosis.Although FTY720 has clinical efficacy, it is a nonselective S1P receptor stimulant, can activate some S1P acceptors, as S1P1, S1P2, S1P3, S1P4, S1P5.Wherein, the combination of FTY720 and S1P3 often causes a series of important side effect, as bradyrhythmia.Therefore, in order to overcome the side effect of FTY720, more single-minded, safer s-generation S1P1 agonist is being found always by many drugmakers and biotech company.
Except improving target spot specificity, shorten important goal that medicine and S1P1 receptor stimulant transformation period in vivo are also screening s-generation S1P1 agonists people such as (, 2013, ACSMedicinalChemistryLetters, 4, p333) Pan.Traditionally, compared with long half-lift small-molecule drug be considered to desirable, because long half time can avoid the frequent use of medicine.But, as immune suppressant drug, the long half-lift of comparatively, become a serious disadvantage, its reason is that it will cause lymphocytic transport to be continued to suppress, peripheral blood lymphocyte number reduces, thus makes medication person's immunologic hypofunction, increases the risk of viral infection.Namely S1P1 receptor stimulant such as the FTY720 of current clinical employing has this defect.When occurring to infect, often need by stopping medicine making peripheral blood lymphocyte number return to normal level as early as possible, so that can quick-recovery immune function of human body soon.The transformation period of FTY720 in human body reaches 4-7 days, even if therefore cut out this medicine, need could recover normally (people such as Budde, 2002 in endolymph cell count for a long time, JournaloftheAmericanSocietyofNephrology, 13:1073-83).
Therefore, what current this area still needed development of new has S1P1 receptor-selective and transformation period shorter S1P1 receptor stimulant, to overcome the defect of existing therapy.
Patent publication CN103450171A discloses the new compound of a class, it is at known following formula 1 compound 1-{4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (the people such as Li, 2005, JournalofMedicinalChemistry, 48 (20) 6169-6173) 2-position on add haloid element or alkyl and obtain.This compounds via vein and oral after, not only maintain immunoregulatory drug effect in external and body, and haloid element replaces the compound of gained all can obviously be reduced through the transformation period of two kinds of administering modes.
In above-mentioned patent, report the synthetic method of adding the new compound of F element on the 2-position of formula 1 compound, but to there is operation comparatively loaded down with trivial details for the method, total recovery is lower, needs the shortcoming of column chromatography purification, is unfavorable for suitability for industrialized production.
Such as, in the preparation of formula 2 compound, need to use a large amount of solvent to adopt the method for column chromatography to carry out the purifying of intermediate compound, cause high cost, thus be unfavorable for suitability for industrialized production.
Therefore, based on the pharmacy value of formula 2 compound in S1P1 receptor stimulant and market potential prospect, need to develop a kind of easy and simple to handle, synthetic method of being easy to suitability for industrialized production.
Summary of the invention
A kind of reaction conditions is simple, aftertreatment is simple and easy to operate, yield is high in order to provide for technical problem to be solved by this invention, process stabilizing be suitable for the synthetic method of formula 2 compound of suitability for industrialized production.
To this, synthetic method disclosed in patent publication CN103450171A has been done a series of improvement by the present invention, by abandoning this solvent load of column chromatography and greatly, easily cause environmental pollution and the operation steps raised the cost and adjust reactant, the solvent and consumption etc. thereof of each reactions steps, achieve the industrial with the scale operation of low cost of formula 2 compound.
In brief, synthetic route of the present invention is as follows:
Specifically, the invention provides the fluoro-4-of 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } synthetic method of-3-azetidinecarboxylic acid, described synthetic method comprises the following steps:
(1) under the existence of condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole, make the fluoro-N'-of the 3-shown in formula 1-3 hydroxy-4-hydroxymethyl methylbenzene carbonamidine and the fluoro-4-of the 2-[5-(4-isobutyl phenenyl)-1 shown in 4-isobutyl-benzoic acid production 1-5 shown in formula 1-4,2,4-oxadiazole-3-base]-phenylcarbinol
(2) the fluoro-4-of the 2-shown in the formula 1-5 [5-(4-isobutyl phenenyl)-1 making step (1) obtain, 2,4-oxadiazole-3-base] the fluoro-4-of the 2-[5-(4-isobutyl phenenyl)-1 shown in-phenylcarbinol and Manganse Dioxide production 1-6,2,4-oxadiazole-3-base]-phenyl aldehyde
(3) take acetic acid as catalyzer, sodium cyanoborohydride is reductive agent, the fluoro-4-of the 2-shown in the formula 1-6 [5-(4-isobutyl phenenyl)-1 that step (3) is obtained, 2,4-oxadiazole-3-base] 3-azetidinecarboxylic acid reaction production 2 compound shown in-phenyl aldehyde and formula 1-7
According to the preferred technical solution of the present invention, after described step (1) is also included in the fluoro-4-of 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-phenylcarbinol shown in production 1-5, the step of the crude product that purifying obtains; Preferably, column chromatography or crystallization operation is adopted to carry out purifying.
When adopting crystallization operation to carry out purifying, recrystallisation solvent be selected from methyl alcohol, ethanol, acetone, methylene dichloride, ethyl acetate and water one or more, be preferably the mixed solvent of first alcohol and water, more preferably volume ratio is the mixed solvent of the first alcohol and water of 3:1; Preferably, the weight of crude product and recrystallisation solvent (than for 1:3-20, is preferably 1:5 in g) volume (in ml).Preferably, at 20 DEG C, crystallization is carried out.
According to the preferred technical solution of the present invention, the reaction of described step (1) is carried out in reaction solvent, described reaction solvent be selected from acetonitrile, N-Methyl pyrrolidone and DMF one or more; Temperature of reaction is 80-140 DEG C; 3-shown in formula 1-3 fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine and the benzoic mol ratio of 4-isobutyl-shown in formula 1-4 are 1:1 ~ 2.0.
Preferably, the reaction solvent of described step (1) is DMF;
Preferably, temperature of reaction is 130-140 DEG C;
Preferably, the fluoro-N'-of the 3-shown in formula 1-3 hydroxy-4-hydroxymethyl methylbenzene carbonamidine and the benzoic mol ratio of 4-isobutyl-shown in formula 1-4 are 1:1 ~ 1.5, are preferably 1:1 ~ 1.2.
According to the preferred technical solution of the present invention, the reaction of described step (2) is carried out in reaction solvent, described reaction solvent be selected from toluene, tetrahydrofuran (THF) and ethyl acetate one or more; The weight of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and reaction solvent is (in g) volume (in ml) than for 1:10-30; Temperature of reaction is 40-70 DEG C; The mol ratio of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and Manganse Dioxide is 1:4 ~ 10.
Preferably, the reaction solvent of described step (2) is ethyl acetate;
Preferably, the weight of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and reaction solvent is (in g) volume (in ml) than for 1:10;
Preferably, temperature of reaction is 60-70 DEG C;
Preferably, the mol ratio of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and Manganse Dioxide is 1:5 ~ 6, is preferably 1:6.
According to the preferred technical solution of the present invention, the reaction of described step (3) is carried out in reaction solvent, and described reaction solvent is tetrahydrofuran (THF) and/or methyl alcohol; The mol ratio of the fluoro-4-of the 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] the 3-azetidinecarboxylic acid shown in-phenyl aldehyde and formula 1-7 is 1:0.5 ~ 6; Temperature of reaction is 0-30 DEG C; Reaction times is 1 ~ 16 hour.
Preferably, the reaction solvent of step (4) is methyl alcohol;
Preferably, the mol ratio mol ratio of the fluoro-4-of the 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] the 3-azetidinecarboxylic acid shown in-phenyl aldehyde and formula 1-7 is 1:1 ~ 1.1, is preferably 1:1;
Preferably, drip after sodium cyanoborohydride being dissolved in methyl alcohol and enter in reaction system, dropping temperature is 0-20 DEG C, is preferably 15-20 DEG C; The mol ratio of the fluoro-4-of the 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde and sodium cyanoborohydride is preferably 1:1;
Preferably, temperature of reaction is 10-20 DEG C, is preferably 15-20 DEG C;
Preferably, the reaction times is 4 ~ 16 hours.
The synthetic method of formula 2 compound of the present invention is the improving one's methods of method disclosed in CN103450171A.Such as, preferred crystallization purifying in step (1) but not the operation of column chromatography carrys out purification of intermediates crude product, greatly, easily cause environmental pollution and the operation steps raised the cost by abandoning this solvent load of column chromatography, thus simplify purification process, avoid the use of a large amount of solvent.In addition, method of the present invention also have adjusted reactant, the solvent and consumption etc. thereof of each reactions steps relative to method disclosed in CN103450171A, in step (2), such as decrease the usage quantity of Manganse Dioxide, thus reduce cost, and use ethyl acetate as solvent, also avoid using tetrahydrofuran (THF), thus evaded issuable security risk; In step (3), use methyl alcohol instead as solvent, reduce the by product generated in reaction, add reaction yield, decrease the quantity of solvent used in reaction.Generally speaking, above-mentioned improvement reduces cost, achieves the scale operation of formula 2 compound industrially low cost, high-level efficiency and security.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is ordinary method.Medicinal raw material used in following embodiment, reagent material etc., if no special instructions, be commercially available purchase product.
Wherein, the fluoro-N'-of the 3-shown in formula 1-3 hydroxy-4-hydroxymethyl methylbenzene carbonamidine can be commercially available, also can according to the 2-in-1 one-tenth of the embodiment of CN103450171A.
In embodiment, compou nd synthesis of the present invention carries out according to the method comprised the steps:
(1)
(2)
(3)
comparative example 1the formula 2 compou nd synthesis method of CN103450171A
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4, 0.819g, 4.60mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 0.882g, 4.60mmol) with I-hydroxybenzotriazole (0.621g, N 4.60mmol), dinethylformamide (10mL) solution stirring adds (Z)-3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3 after 30 minutes, 0.846g, 4.60mmol), gained mixed system heats two hours in 140 DEG C of oil baths, it is complete that liquid chromatography mass spectrometric detects raw material reaction, be cooled to room temperature, the a large amount of N of pressure reducing and steaming, dinethylformamide, with water and extraction into ethyl acetate, gained organic phase is respectively through 0.5N hydrochloric acid soln, saturated sodium bicarbonate solution, water washing, filter after anhydrous sodium sulfate drying, be concentrated into dry, after column chromatography purification, (sherwood oil ~ ethyl acetate=10/1 ~ 4/1 system wash-out) obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-phenylcarbinol (1-5, 0.92g, yield 61%).
Liquid chromatography mass spectrometric display molecular ion peak is MS (ESI): m/z327.0 [M+H]+1HNMR (400MHz, CDCl3) δ: 8.11 (d, J=8.0Hz, 2H), 7.98 (m, 1H), 7.86 (m, 1H), 7.59 (t, J=8.0Hz, 7.6Hz, 1H), 7.33 (d, J=8.0Hz, 2H), 4.85 (s, 2H), 2.57 (d, J=6.8Hz, 2H), 1.93 (m, 1H), 0.93 (d, J=6.8Hz, 6H).
This step aftertreatment is comparatively loaded down with trivial details, and need the method purified product using column chromatography, employ a large amount of solvents in the process of column chromatography, cost is higher, is unsuitable for suitability for industrialized production.
Under (2) 60 degree, the fluoro-4-of 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,0.91g, 2.79mmol) with Manganse Dioxide (2.43g, tetrahydrofuran (THF) (30mL) system of being suspended 27.9mmol) stirs two hours, be cooled to room temperature, filtering and concentrating obtains white solid product, the fluoro-4-of 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,0.90g, yield 99.6%).
Liquid chromatography mass spectrometric display molecular ion peak is MS (ESI): m/z325.0 [M+H]+1HNMR (400MHz, CDCl3) δ: 10.42 (s, 1H), 8.12 ~ 7.99 (m, 5H), 7.34 (d, J=7.2Hz, 2H), 2.58 (d, J=6.4Hz, 2H), 1.93 (m, 1H), 0.93 (d, J=6.4Hz, 6H).
This step employs a large amount of Manganse Dioxide and carries out oxidizing reaction, and carrying out oxidizing reaction owing to using tetrahydrofuran (THF) as solvent has certain security risk, is unsuitable for suitability for industrialized production in this approach.
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-phenyl aldehyde (1-6, 0.90g, 2.78mmol), 3-azetidinecarboxylic acid (1-7, 0.28g, 2.78mmol) and methyl alcohol-tetrahydrofuran (THF) (20mL/20mL) solution stirring two hours of acetic acid (1mL), add sodium cyanoborohydride (1.03g, methanol solution (60mL) 16.35mmol) afterwards room temperature continues stirring 16 hours, filter, with methyl alcohol (10mL) washing leaching cake, dry the fluoro-4-of white solid product 1-{2-[5-(4-isobutyl phenenyl)-1, 2, 4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2) (0.20g, yield 18%).
Liquid chromatography mass spectrometric display molecular ion peak is MS (ESI): m/z410.0 [M+H]+1HNMR (400MHz, CD3OD) δ: 8.13 (d, J=8.4Hz, 2H), 8.05 (m, 1H), 7.97 (m, 1H), 7.68 (t, J=8.0Hz, 7.6Hz, 1H), 7.42 (d, J=8.4Hz, 2H), 4.40 (s, 2H), 4.15 (m, 4H), 3.41 (m, 1H), 2.61 (d, J=7.2Hz, 2H), 1.95 (m, 1H), 0.94 (d, J=7.2Hz, 6H).
This method employs a large amount of solvents and reacts, and make the cost of reaction higher, meanwhile, reaction yield is lower, is unsuitable for suitability for industrialized production.
embodiment 1the screening of synthetic method of the present invention---step (1)
According to step (1) the Preparation and characterization formula 1-5 crude compound of comparative example 1, detecting purity through LCMS is 77.25%.
Obtained crude product is carried out the screening of crystallization purifying condition.Crystallization operation for dissolve crude product with recrystallisation solvent, and at 20 DEG C crystallization, filter, obtaining off-white color solid product after vacuum-drying is the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol, detects purity through LCMS.
First listed by table 1, above-mentioned crystallization operation is carried out, to filter out preferred recrystallisation solvent.
The solvent of table 1. crystallization purifying and the screening of consumption thereof
As known from Table 1, in the crystallization condition using single solvent, methyl alcohol and ethanol is used to promote obvious as solvent for the purity of product.The relative ethanol of yield of methyl alcohol is high a lot, but also only has 55.4%.Use pure water substantially not promote as the purity of solvent to product, but lose less, so attempt the mixed solvent of first alcohol and water as recrystallisation solvent in follow-up research.
Next, listed by table 2, above-mentioned crystallization operation purifying is carried out, to filter out the preferred proportion of the mixed solvent of first alcohol and water.Wherein the weight of crude product and mixed crystallization solvent is (in g) volume (in ml) than for 1:5.
The screening of table 2 mixed solvent ratio
As known from Table 2, improve the amount of methyl alcohol in mixed solvent, can the purity of improving product, but yield decreases; Improve the amount of water, the yield of purifying can be promoted, but the purity of product decreases.Consider, choose methyl alcohol and water volume ratio is that the condition of 3:1 is as ratio in crystallized mixed solvent.
Then, listed by table 3, carry out above-mentioned crystallization operation, to filter out the preferable amount of mixed solvent.Wherein in mixed solvent, methyl alcohol and water volume ratio are 3:1.
The screening of table 3 solvent load
As known from Table 3, when use crude product weight and mixed solvent volume ratio are 1g:5ml, yield and the purity of product are higher; When use crude product weight and mixed solvent volume ratio are 1g:20ml, although the purity of product is higher relative to 1g:5ml, have lost more yield, so choose crude product weight and mixed solvent volume ratio is the solvent system of 1g:5ml as crystallization.
embodiment 2the screening of synthetic method of the present invention---step (2)
The step (2) of the inventive method is carried out according to following process:
The fluoro-4-of 2-shown in the formula 1-5 obtain embodiment 1 purifying [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol is dissolved in reaction solvent, then adds activated manganese dioxide.Reaction solution is heated to reflux and continue reaction after, be cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-phenyl aldehyde shown in white solid product type 1-6, detects transformation efficiency through LCMS.
First listed by table 4, above-mentioned synthesis step is carried out, to filter out preferred reaction solvent.The mol ratio of the fluoro-4-of the 2-shown in its Chinese style 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and Manganse Dioxide is 1:6.Raw material in table 4-6 refers to the fluoro-4-of 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-phenylcarbinol shown in formula 1-5.
The screening of table 4 reaction solvent
As known from Table 4, tetrahydrofuran (THF), ethyl acetate, toluene is used to affect less as reaction solvent on the transformation efficiency of reaction and yield.But tetrahydrofuran (THF) carries out as solvent the risk that oxidizing reaction has security, and toluene toxicity is higher, therefore select ethyl acetate as reaction solvent.
Next, ethyl acetate, as reaction solvent, carries out above-mentioned synthesis step listed by table 5, to filter out preferred solvent load.The mol ratio of the fluoro-4-of the 2-shown in its Chinese style 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and Manganse Dioxide is 1:6.
The screening of table 5 reaction solvent consumption
As known from Table 5, the weightmeasurement ratio of Materials Solvents is that 1g:10ml, 1g:20ml, 1g:30ml affect less for the transformation efficiency reacted and yield, considers, select the solvent load using the ratio of 1g:10ml as reaction with cost aspect.
Then, listed by table 6, carry out above-mentioned synthesis step, to filter out preferred oxygenant Manganse Dioxide consumption.Wherein the fluoro-4-of 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-phenylcarbinol shown in formula 1-5 and ethyl acetate is used to be the consumption of 1g:10ml.
The screening of table 6 oxygenant consumption
As known from Table 6, when using the mol ratio of raw material and Manganse Dioxide for 1:6, reaction conversion ratio and yield higher, when both the consumption of Manganse Dioxide is increased to, mol ratio is 1:10, affect less for the transformation efficiency reacted and yield, from the viewpoint of cost and yield, select 1:6 as the usage quantity of the two.
embodiment 3the screening of synthetic method of the present invention---step (3)
The step (3) of the inventive method is carried out according to following process:
At room temperature, the 3-azetidinecarboxylic acid shown in fluoro-for the 2-shown in formula 1-6 4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde, formula 1-7 and Glacial acetic acid are joined in reaction solvent, stir 2 hours at 20 DEG C.NaBH3CN is dissolved in methyl alcohol, then in 1 hour, the methanol solution of NaBH3CN is added drop-wise in reaction system, after dropwising, stirring reaction at 20 DEG C.Reacting liquid filtering, filter cake methyl alcohol drip washing post-drying, obtains formula 2 compound and the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid, detect transformation efficiency through LCMS.
First listed by table 7, above-mentioned synthesis step is carried out, to filter out preferred reaction solvent.The fluoro-4-of 2-shown in its Chinese style 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] mol ratio of the 3-azetidinecarboxylic acid shown in-phenyl aldehyde and formula 1-7 is 1:1.05, the fluoro-4-of 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] mol ratio of-phenyl aldehyde and sodium cyanoborohydride be the methanol solution dropping temperature of 1:1, NaBH3CN is 15 ~ 20 DEG C.Raw material in table 7-9 refers to the fluoro-4-of 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-the base]-phenyl aldehyde shown in formula 1-6.
The screening of table 7 reaction solvent
| Solvent | Solvent load | Reaction times | Transformation efficiency (LCMS) | Yield |
| (raw material: solvent) | ||||
| Tetrahydrofuran (THF) | 1g:40ml | 6h | 1.64％ | |
| Methyl alcohol | 1g:40ml | 6h | 79.26％ | 69.10％ |
| Ethanol | 1g:40ml | 6h | 66.20％ | 53.23％ |
As known from Table 7, use tetrahydrofuran (THF) as reaction solvent, reaction conversion ratio is very low, and uses methanol phase for ethanol as reaction solvent, and reaction conversion ratio and yield are all higher.
Next, listed by table 8, carry out above-mentioned synthesis step, to filter out preferred reductive agent consumption.The fluoro-4-of 2-shown in its Chinese style 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] mol ratio of the 3-azetidinecarboxylic acid shown in-phenyl aldehyde and formula 1-7 is 1:1.05, reaction solvent is methyl alcohol, and the methanol solution dropping temperature of NaBH3CN is 15 ~ 20 DEG C.
The screening of table 8 reductive agent consumption
As known from Table 8, when using raw material and sodium cyanoborohydride mol ratio for 1:1, the transformation efficiency of reaction, yield and product purity are all higher.
Then, listed by table 9, carry out above-mentioned synthesis step, to filter out preferred reductive agent dropping temperature.The mol ratio of the fluoro-4-of the 2-shown in its Chinese style 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] the 3-azetidinecarboxylic acid shown in-phenyl aldehyde and formula 1-7 is 1:1.05, and reaction solvent is methyl alcohol.
Table 9 reacts the screening of dropping temperature
As known from Table 9, use the sodium cyanoborohydride dropping temperature of 15-20 DEG C, transformation efficiency and the product purity of reaction are higher.
embodiment 4synthetic method of the present invention
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4,0.148Kg, 0.83mol) be dissolved in N, in dinethylformamide (1.7L), add I-hydroxybenzotriazole (0.11Kg again, 0.83mol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.16Kg, 0.83mol), be heated to 30 DEG C and continue stirring after 30 minutes, add 3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3,0.153Kg, 0.83mol).Reaction solution be heated to 140 DEG C and continue reaction after 2 hours, being cooled to room temperature.Concentrating under reduced pressure removes N, dinethylformamide, enriched material is dissolved in ethyl acetate (2.0L), and use water (1.5L × 2) respectively, saturated sodium bicarbonate solution (1.5L) washs, collect organic phase with after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 256g crude product.
Above-mentioned crude product 1.28L methyl alcohol and water mixed solvent (volume ratio 3:1) recrystallization, and in 20 DEG C of crystallizatioies, filter, the fluoro-4-of off-white color solid product 2-[5-(4-isobutyl phenenyl)-1 is obtained after vacuum-drying, 2,4-oxadiazole-3-base]-phenylcarbinol (1-5,182g, yield 71%), detecting purity through LCMS is 93.1%.
MS(ESI):m/z327.0[M+H]+1HNMR(400MHz,CDCl3)δ:8.11(d,J＝8.0Hz,2H),7.98(m,1H),7.86(m,1H),7.59(t,J＝8.0Hz,7.6Hz,1H),7.33(d,J＝8.0Hz,2H),4.85(s,2H),2.57(d,J＝6.8Hz,2H),1.93(m,1H),0.93(d,J＝6.8Hz,6H).
(2) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,0.14Kg, 0.43mol) be dissolved in ethyl acetate (1.4L), then add activated manganese dioxide (0.21Kg, 2.42mol).Reaction solution be heated to reflux and continue reaction after 3 hours, being cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,139g, yield 99.0%), detect purity 97.6% through LCMS.
MS(ESI):m/z325.0[M+H]+1HNMR(400MHz,CDCl3)δ:10.42(s,1H),8.12～7.99(m,5H),7.34(d,J＝7.2Hz,2H),2.58(d,J＝6.4Hz,2H),1.93(m,1H),0.93(d,J＝6.4Hz,6H).
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,60g, 0.185mol), 3-azetidinecarboxylic acid (1-7,19.5g, 0.193mol) and Glacial acetic acid (360mL, 0.63mol) join in methyl alcohol (1.6L), stir 2 hours at 20 DEG C.By NaBH3CN (11.5g, 0.185mol) be dissolved in methyl alcohol (200mL), then in 1 hour, the methanol solution of NaBH3CN be added drop-wise in reaction system, control dropping temperature between 15-20 DEG C, after dropwising, react and stir 16 hours at 20 DEG C.Reacting liquid filtering, filter cake 300mL methyl alcohol drip washing post-drying, obtain the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2,67g, yield 89.0%), the purity detected through LC-MS is 98.8%.
MS(ESI):m/z410.2[M+H]+；1HNMR(400MHz,CDCl3)δ:8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
embodiment 5synthetic method of the present invention
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4,1.477Kg, 8.30mol) be dissolved in N, in dinethylformamide (17L), add I-hydroxybenzotriazole (1.12Kg again, 8.30mol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.58Kg, 8.30mol), be heated to 30 DEG C and continue stirring after 30 minutes, add 3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3,1.527Kg, 8.30mol).Reaction solution be heated to 140 DEG C and continue reaction after 2 hours, being cooled to room temperature.Concentrating under reduced pressure removes DMF, enriched material is dissolved in ethyl acetate (20L), and use water (15L × 2) respectively, saturated sodium bicarbonate solution (15L) washing, collects organic phase and with after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 2.6Kg crude product.
Above-mentioned crude product 12.5L methyl alcohol and water mixed solvent (volume ratio 3:1) recrystallization, and in 20 DEG C of crystallizatioies, filter, the fluoro-4-of off-white color solid product 2-[5-(4-isobutyl phenenyl)-1 is obtained after vacuum-drying, 2,4-oxadiazole-3-base]-phenylcarbinol (1-5,1.9Kg, yield 73%), detecting purity through LCMS is 93.89%.
MS(ESI):m/z327.0[M+H]+1HNMR(400MHz,CDCl3)δ:8.11(d,J＝8.0Hz,2H),7.98(m,1H),7.86(m,1H),7.59(t,J＝8.0Hz,7.6Hz,1H),7.33(d,J＝8.0Hz,2H),4.85(s,2H),2.57(d,J＝6.8Hz,2H),1.93(m,1H),0.93(d,J＝6.8Hz,6H).
(2) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,1.4Kg, 4.30mol) be dissolved in ethyl acetate (14L), then add activated manganese dioxide (2.1Kg, 24.15mol).Reaction solution be heated to reflux and continue reaction after 3 hours, being cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,1.38kg, yield 99.0%), detect purity 93.94% through LCMS.
MS(ESI):m/z325.0[M+H]+1HNMR(400MHz,CDCl3)δ:10.42(s,1H),8.12～7.99(m,5H),7.34(d,J＝7.2Hz,2H),2.58(d,J＝6.4Hz,2H),1.93(m,1H),0.93(d,J＝6.4Hz,6H).
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,0.6kg, 1.85mol), 3-azetidinecarboxylic acid (1-7,0.195kg, 1.93mol) and Glacial acetic acid (0.360L, 6.3mol) join in methyl alcohol (16L), stir 2 hours at 20 DEG C.By NaBH3CN (0.115kg, 1.85mol) be dissolved in methyl alcohol (2L), be then added drop-wise in reaction system by the methanol solution of NaBH3CN in 1 hour, control temperature is between 15-20 DEG C, after dropwising, react and stir 16 hours at 20 DEG C.Reacting liquid filtering, filter cake 3L methyl alcohol drip washing post-drying, obtain the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2,0.7kg, yield 92.6%), the purity detected through LC-MS is 97.6%.
MS(ESI):m/z410.2[M+H]+；1HNMR(400MHz,CDCl3)δ:8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
embodiment 6synthetic method of the present invention
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4,0.148Kg, 0.83mol) be dissolved in N, in dinethylformamide (1.7L), add I-hydroxybenzotriazole (0.11Kg again, 0.83mol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.16Kg, 0.83mol), be heated to 30 DEG C and continue stirring after 30 minutes, add 3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3,0.153Kg, 0.83mol).Reaction solution be heated to 140 DEG C and continue reaction after 2 hours, being cooled to room temperature.Concentrating under reduced pressure removes N, dinethylformamide, enriched material is dissolved in ethyl acetate (2.0L), and use water (1.5L × 2) respectively, saturated sodium bicarbonate solution (1.5L) washs, collect organic phase with after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 251g crude product.
Above-mentioned crude product 1.28L methyl alcohol and water mixed solvent (volume ratio 1:1) recrystallization, and in 20 DEG C of crystallizatioies, filter, the fluoro-4-of off-white color solid product 2-[5-(4-isobutyl phenenyl)-1 is obtained after vacuum-drying, 2,4-oxadiazole-3-base]-phenylcarbinol (1-5,158g, yield 63%), detecting purity through LCMS is 92.1%.
MS(ESI):m/z327.0[M+H]+1HNMR(400MHz,CDCl3)δ:8.11(d,J＝8.0Hz,2H),7.98(m,1H),7.86(m,1H),7.59(t,J＝8.0Hz,7.6Hz,1H),7.33(d,J＝8.0Hz,2H),4.85(s,2H),2.57(d,J＝6.8Hz,2H),1.93(m,1H),0.93(d,J＝6.8Hz,6H).
(2) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,0.14Kg, 0.43mol) be dissolved in ethyl acetate (1.4L), then add activated manganese dioxide (0.19Kg, 2.15mol).Reaction solution be heated to reflux and continue reaction after 3 hours, being cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,138g, yield 99%), detect purity 98.5% through LCMS.
MS(ESI):m/z325.0[M+H]+1HNMR(400MHz,CDCl3)δ:10.42(s,1H),8.12～7.99(m,5H),7.34(d,J＝7.2Hz,2H),2.58(d,J＝6.4Hz,2H),1.93(m,1H),0.93(d,J＝6.4Hz,6H).
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,60g, 0.185mol), 3-azetidinecarboxylic acid (1-7,19.5g, 0.193mol) and Glacial acetic acid (360mL, 0.63mol) join in methyl alcohol (1.6L), stir 2 hours at 20 DEG C.By NaBH3CN (5.8g, 0.09mol) be dissolved in methyl alcohol (200mL), then in 1 hour, the methanol solution of NaBH3CN be added drop-wise in reaction system, control dropping temperature between 15-20 DEG C, after dropwising, react and stir 16 hours at 20 DEG C.Reacting liquid filtering, filter cake 300mL methyl alcohol drip washing post-drying, obtain the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2,62g, yield 81.9%), the purity detected through LC-MS is 94.6%.
MS(ESI):m/z410.2[M+H]+；1HNMR(400MHz,CDCl3)δ:8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
embodiment 7synthetic method of the present invention
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4,0.148Kg, 0.83mol) be dissolved in N, in dinethylformamide (1.7L), add I-hydroxybenzotriazole (0.11Kg again, 0.83mol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.16Kg, 0.83mol), be heated to 30 DEG C and continue stirring after 30 minutes, add 3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3,0.153Kg, 0.83mol).Reaction solution be heated to 140 DEG C and continue reaction after 2 hours, being cooled to room temperature.Concentrating under reduced pressure removes N, dinethylformamide, enriched material is dissolved in ethyl acetate (2.0L), and use water (1.5L × 2) respectively, saturated sodium bicarbonate solution (1.5L) washs, collect organic phase with after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 260g crude product.
Above-mentioned crude product 1.30L methyl alcohol and water mixed solvent (volume ratio 1:3) recrystallization, and in 20 DEG C of crystallizatioies, filter, the fluoro-4-of off-white color solid product 2-[5-(4-isobutyl phenenyl)-1 is obtained after vacuum-drying, 2,4-oxadiazole-3-base]-phenylcarbinol (1-5,196g, yield 76%), detecting purity through LCMS is 88.7%.
MS(ESI):m/z327.0[M+H]+1HNMR(400MHz,CDCl3)δ:8.11(d,J＝8.0Hz,2H),7.98(m,1H),7.86(m,1H),7.59(t,J＝8.0Hz,7.6Hz,1H),7.33(d,J＝8.0Hz,2H),4.85(s,2H),2.57(d,J＝6.8Hz,2H),1.93(m,1H),0.93(d,J＝6.8Hz,6H).
(2) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,0.14Kg, 0.43mol) be dissolved in ethyl acetate (1.4L), then add activated manganese dioxide (0.21Kg, 2.42mol).Reaction solution be heated to reflux and continue reaction after 3 hours, being cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,139g, yield 99%), detect purity 97.7% through LCMS.
MS(ESI):m/z325.0[M+H]+1HNMR(400MHz,CDCl3)δ:10.42(s,1H),8.12～7.99(m,5H),7.34(d,J＝7.2Hz,2H),2.58(d,J＝6.4Hz,2H),1.93(m,1H),0.93(d,J＝6.4Hz,6H).
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,60g, 0.185mol), 3-azetidinecarboxylic acid (1-7,19.5g, 0.193mol) and Glacial acetic acid (360mL, 0.63mol) join in methyl alcohol (1.6L), stir 2 hours at 20 DEG C.By NaBH3CN (23.0g, 0.37mol) be dissolved in methyl alcohol (200mL), then in 1 hour, the methanol solution of NaBH3CN be added drop-wise in reaction system, control dropping temperature between 15-20 DEG C, after dropwising, react and stir 16 hours at 20 DEG C.Reacting liquid filtering, filter cake 300mL methyl alcohol drip washing post-drying, obtain the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2,60g, yield 79.0%), the purity detected through LC-MS is 94.2%.
MS(ESI):m/z410.2[M+H]+；1HNMR(400MHz,CDCl3)δ:8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
embodiment 8synthetic method of the present invention
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4,0.148Kg, 0.83mol) be dissolved in N, in dinethylformamide (1.7L), add I-hydroxybenzotriazole (0.11Kg again, 0.83mol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.16Kg, 0.83mol), be heated to 30 DEG C and continue stirring after 30 minutes, add 3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3,0.153Kg, 0.83mol).Reaction solution be heated to 140 DEG C and continue reaction after 2 hours, being cooled to room temperature.Concentrating under reduced pressure removes N, dinethylformamide, enriched material is dissolved in ethyl acetate (2.0L), and use water (1.5L × 2) respectively, saturated sodium bicarbonate solution (1.5L) washs, collect organic phase with after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 250g crude product.
Above-mentioned crude product 1.25L methyl alcohol and water mixed solvent (volume ratio 2:1) recrystallization, and in 20 DEG C of crystallizatioies, filter, the fluoro-4-of off-white color solid product 2-[5-(4-isobutyl phenenyl)-1 is obtained after vacuum-drying, 2,4-oxadiazole-3-base]-phenylcarbinol (1-5,169g, yield 68%), detecting purity through LCMS is 93.9%.
MS(ESI):m/z327.0[M+H]+1HNMR(400MHz,CDCl3)δ:8.11(d,J＝8.0Hz,2H),7.98(m,1H),7.86(m,1H),7.59(t,J＝8.0Hz,7.6Hz,1H),7.33(d,J＝8.0Hz,2H),4.85(s,2H),2.57(d,J＝6.8Hz,2H),1.93(m,1H),0.93(d,J＝6.8Hz,6H).
(2) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,0.14Kg, 0.43mol) be dissolved in ethyl acetate (1.4L), then add activated manganese dioxide (0.37Kg, 4.3mol).Reaction solution be heated to reflux and continue reaction after 3 hours, being cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,139g, yield 99%), detect purity 99.2% through LCMS.
MS(ESI):m/z325.0[M+H]+1HNMR(400MHz,CDCl3)δ:10.42(s,1H),8.12～7.99(m,5H),7.34(d,J＝7.2Hz,2H),2.58(d,J＝6.4Hz,2H),1.93(m,1H),0.93(d,J＝6.4Hz,6H).
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,60g, 0.185mol), 3-azetidinecarboxylic acid (1-7,19.5g, 0.193mol) and Glacial acetic acid (360mL, 0.63mol) join in methyl alcohol (1.6L), stir 2 hours at 20 DEG C.By NaBH3CN (69.0g, 1.11mol) be dissolved in methyl alcohol (200mL), then in 1 hour, the methanol solution of NaBH3CN be added drop-wise in reaction system, control dropping temperature between 15-20 DEG C, after dropwising, react and stir 16 hours at 20 DEG C.Reacting liquid filtering, filter cake 300mL methyl alcohol drip washing post-drying, obtain the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2,54g, yield 71.2%), the purity detected through LC-MS is 94.4%.
MS(ESI):m/z410.2[M+H]+；1HNMR(400MHz,CDCl3)δ:8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
embodiment 9synthetic method of the present invention
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4,0.148Kg, 0.83mol) be dissolved in N, in dinethylformamide (1.7L), add I-hydroxybenzotriazole (0.11Kg again, 0.83mol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.16Kg, 0.83mol), be heated to 30 DEG C and continue stirring after 30 minutes, add 3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3,0.153Kg, 0.83mol).Reaction solution be heated to 140 DEG C and continue reaction after 2 hours, being cooled to room temperature.Concentrating under reduced pressure removes N, dinethylformamide, enriched material is dissolved in ethyl acetate (2.0L), and use water (1.5L × 2) respectively, saturated sodium bicarbonate solution (1.5L) washs, collect organic phase with after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 256g crude product.
Above-mentioned crude product 1.28L methyl alcohol and water mixed solvent (volume ratio 1:2) recrystallization, and in 20 DEG C of crystallizatioies, filter, the fluoro-4-of off-white color solid product 2-[5-(4-isobutyl phenenyl)-1 is obtained after vacuum-drying, 2,4-oxadiazole-3-base]-phenylcarbinol (1-5,190g, yield 74%), detecting purity through LCMS is 92.6%.
MS(ESI):m/z327.0[M+H]+1HNMR(400MHz,CDCl3)δ:8.11(d,J＝8.0Hz,2H),7.98(m,1H),7.86(m,1H),7.59(t,J＝8.0Hz,7.6Hz,1H),7.33(d,J＝8.0Hz,2H),4.85(s,2H),2.57(d,J＝6.8Hz,2H),1.93(m,1H),0.93(d,J＝6.8Hz,6H).
(2) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,0.14Kg, 0.43mol) be dissolved in ethyl acetate (1.4L), then add activated manganese dioxide (0.15Kg, 1.72mol).Reaction solution be heated to reflux and continue reaction after 3 hours, being cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,139g, yield 99%), detect purity 96.9% through LCMS.
MS(ESI):m/z325.0[M+H]+1HNMR(400MHz,CDCl3)δ:10.42(s,1H),8.12～7.99(m,5H),7.34(d,J＝7.2Hz,2H),2.58(d,J＝6.4Hz,2H),1.93(m,1H),0.93(d,J＝6.4Hz,6H).
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,60g, 0.185mol), 3-azetidinecarboxylic acid (1-7,19.5g, 0.193mol) and Glacial acetic acid (360mL, 0.63mol) join in methyl alcohol (1.6L), stir 2 hours at 20 DEG C.By NaBH3CN (11.5g, 0.185mol) be dissolved in methyl alcohol (200mL), then in 1 hour, the methanol solution of NaBH3CN be added drop-wise in reaction system, control dropping temperature between 15-20 DEG C, after dropwising, react and stir 16 hours at 20 DEG C.Reacting liquid filtering, filter cake 300mL methyl alcohol drip washing post-drying, obtain the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2,64g, yield 84.4%), the purity detected through LC-MS is 95.5%.
MS(ESI):m/z410.2[M+H]+；1HNMR(400MHz,CDCl3)δ:8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
embodiment 10synthetic method of the present invention
(1) under room temperature, by 4-isobutyl-benzene formic acid (1-4,0.148Kg, 0.83mol) be dissolved in N, in dinethylformamide (1.7L), add I-hydroxybenzotriazole (0.11Kg again, 0.83mol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.16Kg, 0.83mol), be heated to 30 DEG C and continue stirring after 30 minutes, add 3-fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine (1-3,0.153Kg, 0.83mol).Reaction solution be heated to 140 DEG C and continue reaction after 2 hours, being cooled to room temperature.Concentrating under reduced pressure removes N, dinethylformamide, enriched material is dissolved in ethyl acetate (2.0L), and use water (1.5L × 2) respectively, saturated sodium bicarbonate solution (1.5L) washs, collect organic phase with after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 258g crude product.
Above-mentioned crude product 1.29L methyl alcohol and water mixed solvent (volume ratio 3:1) recrystallization, and in 20 DEG C of crystallizatioies, filter, the fluoro-4-of off-white color solid product 2-[5-(4-isobutyl phenenyl)-1 is obtained after vacuum-drying, 2,4-oxadiazole-3-base]-phenylcarbinol (1-5,186g, yield 72%), detecting purity through LCMS is 93.8%.
MS(ESI):m/z327.0[M+H]+1HNMR(400MHz,CDCl3)δ:8.11(d,J＝8.0Hz,2H),7.98(m,1H),7.86(m,1H),7.59(t,J＝8.0Hz,7.6Hz,1H),7.33(d,J＝8.0Hz,2H),4.85(s,2H),2.57(d,J＝6.8Hz,2H),1.93(m,1H),0.93(d,J＝6.8Hz,6H).
(2) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol (1-5,0.14Kg, 0.43mol) be dissolved in ethyl acetate (2.8L), then add activated manganese dioxide (0.21Kg, 2.42mol).Reaction solution be heated to reflux and continue reaction after 3 hours, being cooled to room temperature.Filter and collect light yellow filtrate, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains the fluoro-4-of white solid product 2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,138g, yield 99%), detect purity 98.8% through LCMS.
MS(ESI):m/z325.0[M+H]+1HNMR(400MHz,CDCl3)δ:10.42(s,1H),8.12～7.99(m,5H),7.34(d,J＝7.2Hz,2H),2.58(d,J＝6.4Hz,2H),1.93(m,1H),0.93(d,J＝6.4Hz,6H).
(3) under room temperature, by fluoro-for 2-4-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde (1-6,60g, 0.185mol), 3-azetidinecarboxylic acid (1-7,19.5g, 0.193mol) and Glacial acetic acid (360mL, 0.63mol) join in methyl alcohol (1.6L), stir 2 hours at 20 DEG C.By NaBH3CN (11.5g, 0.185mol) be dissolved in methyl alcohol (200mL), then in 1 hour, the methanol solution of NaBH3CN be added drop-wise in reaction system, control dropping temperature between 5-15 DEG C, after dropwising, react and stir 16 hours at 20 DEG C.Reacting liquid filtering, filter cake 300mL methyl alcohol drip washing post-drying, obtain the fluoro-4-of white solid 1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl }-3-azetidinecarboxylic acid (compound 2,64g, yield 84.5%), the purity detected through LC-MS is 96.9%.
MS(ESI):m/z410.2[M+H]+；1HNMR(400MHz,CDCl3)δ:8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H).
Specific description of embodiments of the present invention does not above limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (9)
- The fluoro-4-of 1.1-{2-[5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-benzyl } synthetic method of-3-azetidinecarboxylic acid, described synthetic method comprises the following steps:(1) under the existence of condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole, make the fluoro-N'-of the 3-shown in formula 1-3 hydroxy-4-hydroxymethyl methylbenzene carbonamidine and the fluoro-4-of the 2-[5-(4-isobutyl phenenyl)-1 shown in 4-isobutyl-benzoic acid production 1-5 shown in formula 1-4,2,4-oxadiazole-3-base]-phenylcarbinol(2) the fluoro-4-of the 2-shown in the formula 1-5 [5-(4-isobutyl phenenyl)-1 making step (1) obtain, 2,4-oxadiazole-3-base] the fluoro-4-of the 2-[5-(4-isobutyl phenenyl)-1 shown in-phenylcarbinol and Manganse Dioxide production 1-6,2,4-oxadiazole-3-base]-phenyl aldehyde(3) take acetic acid as catalyzer, sodium cyanoborohydride is reductive agent, the fluoro-4-of the 2-shown in the formula 1-6 [5-(4-isobutyl phenenyl)-1 that step (3) is obtained, 2,4-oxadiazole-3-base] 3-azetidinecarboxylic acid reaction production 2 compound shown in-phenyl aldehyde and formula 1-7
- 2. synthetic method according to claim 1, it is characterized in that, described step (1) is also included in the fluoro-4-of the 2-[5-(4-isobutyl phenenyl)-1,2 shown in production 1-5,4-oxadiazole-3-base] after-phenylcarbinol, the step of the crude product that purifying obtains;Preferably, column chromatography or crystallization operation is adopted to carry out purifying.
- 3. synthetic method according to claim 2, it is characterized in that, in described crystallization operation, recrystallisation solvent be selected from methyl alcohol, ethanol, acetone, methylene dichloride, ethyl acetate and water one or more, be preferably the mixed solvent of first alcohol and water, more preferably volume ratio is the mixed solvent of the first alcohol and water of 3:1;Preferably, the weight of crude product and recrystallisation solvent (than for 1:3-20, is preferably 1:5 in g) volume (in ml);Preferably, at 20 DEG C, crystallization is carried out.
- 4. synthetic method according to any one of claim 1 to 3, it is characterized in that, the reaction of described step (1) is carried out in reaction solvent, described reaction solvent be selected from acetonitrile, N-Methyl pyrrolidone and DMF one or more; Temperature of reaction is 80-140 DEG C; 3-shown in formula 1-3 fluoro-N'-hydroxy-4-hydroxymethyl methylbenzene carbonamidine and the benzoic mol ratio of 4-isobutyl-shown in formula 1-4 are 1:1 ~ 2.
- 5. synthetic method according to any one of claim 1 to 4, is characterized in that, the reaction solvent of described step (1) is DMF;Preferably, temperature of reaction is 130-140 DEG C;Preferably, the fluoro-N'-of the 3-shown in formula 1-3 hydroxy-4-hydroxymethyl methylbenzene carbonamidine and the benzoic mol ratio of 4-isobutyl-shown in formula 1-4 are 1:1 ~ 1.5, are preferably 1:1 ~ 1.2.
- 6. synthetic method according to any one of claim 1 to 5, is characterized in that, the reaction of described step (2) is carried out in reaction solvent, described reaction solvent be selected from toluene, tetrahydrofuran (THF) and ethyl acetate one or more; The weight of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and reaction solvent is (in g) volume (in ml) than for 1:10-30; Temperature of reaction is 40-70 DEG C; The mol ratio of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and Manganse Dioxide is 1:4 ~ 10.
- 7. synthetic method according to any one of claim 1 to 6, is characterized in that, the reaction solvent of described step (2) is ethyl acetate;Preferably, the weight of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and reaction solvent is (in g) volume (in ml) than for 1:10;Preferably, temperature of reaction is 60-70 DEG C;Preferably, the mol ratio of the fluoro-4-of the 2-shown in formula 1-5 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenylcarbinol and Manganse Dioxide is 1:5 ~ 6, is preferably 1:6.
- 8. synthetic method according to any one of claim 1 to 7, is characterized in that, the reaction of described step (3) is carried out in reaction solvent, and described reaction solvent is tetrahydrofuran (THF) and/or methyl alcohol; The mol ratio of the fluoro-4-of the 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] the 3-azetidinecarboxylic acid shown in-phenyl aldehyde and formula 1-7 is 1:1 ~ 1.2; The mol ratio of the fluoro-4-of the 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde and sodium cyanoborohydride is 1:0.5 ~ 6; Temperature of reaction is 0-30 DEG C; Reaction times is 1 ~ 16 hour.
- 9. synthetic method according to any one of claim 1 to 8, is characterized in that, the reaction solvent of step (3) is methyl alcohol;Preferably, the mol ratio of the fluoro-4-of the 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base] the 3-azetidinecarboxylic acid shown in-phenyl aldehyde and formula 1-7 is 1:1 ~ 1.1, is preferably 1:1;Preferably, drip after sodium cyanoborohydride being dissolved in methyl alcohol and enter in reaction system, dropping temperature is 0-20 DEG C, is preferably 15-20 DEG C; The mol ratio of the fluoro-4-of the 2-shown in formula 1-6 [5-(4-isobutyl phenenyl)-1,2,4-oxadiazole-3-base]-phenyl aldehyde and sodium cyanoborohydride is preferably 1:1;Temperature of reaction is 10-20 DEG C, is preferably 15-20 DEG C;Preferably, the reaction times is 4 ~ 16 hours.
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| US11512078B2 (en) | 2018-05-04 | 2022-11-29 | Suzhou Connect Biopharmaceuticals, Ltd. | Addition salt of S1P1 receptor agonist and crystal form thereof, and pharmaceutical composition |
| RU2822288C2 (en) * | 2018-05-04 | 2024-07-03 | Сучжоу Коннект Байофармасьютикалз, Лтд. | Addition salt of the s1p1 receptor agonist and its crystalline form and pharmaceutical composition based on it |
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| CN103450171A (en) * | 2013-09-22 | 2013-12-18 | 苏州康乃德生物医药有限公司 | Novel immune adjustment compound, application thereof and medicine combination comprising same |
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| ZHEN LI ET AL.: "Discovery of Potent 3,5-Diphenyl-1,2,4-oxadiazole Sphingosine-1-phosphate-1 (S1P1) Receptor Agonists with Exceptional Selectivity against S1P2 and S1P3", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299412A (en) * | 2017-01-11 | 2018-07-20 | 苏州康乃德生物医药有限公司 | The addition salts and its crystal form and pharmaceutical composition of a kind of S1P1 receptor stimulating agents |
| CN108299412B (en) * | 2017-01-11 | 2021-02-09 | 苏州康乃德生物医药有限公司 | Addition salt of S1P1 receptor agonist, crystal form and pharmaceutical composition thereof |
| CN115772166A (en) * | 2017-01-11 | 2023-03-10 | 苏州康乃德生物医药有限公司 | Addition salt of S1P1 receptor agonist, crystal form and pharmaceutical composition thereof |
| US11512078B2 (en) | 2018-05-04 | 2022-11-29 | Suzhou Connect Biopharmaceuticals, Ltd. | Addition salt of S1P1 receptor agonist and crystal form thereof, and pharmaceutical composition |
| RU2822288C2 (en) * | 2018-05-04 | 2024-07-03 | Сучжоу Коннект Байофармасьютикалз, Лтд. | Addition salt of the s1p1 receptor agonist and its crystalline form and pharmaceutical composition based on it |
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