A kind of preparation method of serinol

Abstract

The invention provides a low-cost and easy-to-operate method for preparing serinol, which comprises the following steps: step 1: adding 3-halogenated propylene of formula I into ammonia water, adding peroxide, and reacting to generate 1,2-oxyazetidine-3-carboxaldehyde of formula II; step 2: hydrogenating and reducing the 1,2-oxyazetidine-3-carboxaldehyde of formula II to open the ring, so as to obtain serinol.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing serinol. Background Art

[0002] Serinol (chemical name: 2-amino-1,3-propanediol) is a pharmaceutical intermediate and the main raw material for synthesizing iopamidol (pharmaceutical name: iodine). Iopamidol is a non-ionic contrast agent and has been widely used as a diagnostic reagent for the blood system, lymphatic system, urinary system, and nervous system. Its demand has increased year by year, but due to the limitation of technical level, the production of this product has not been able to meet the demand. The demand gap in my country alone has reached nearly 1,000 tons.

[0003] At present, the synthetic process routes of serinol that have been developed at home and abroad mainly include the synthetic route of catalytic decomposition of dihydroxyacetone oxime, which requires the use of expensive catalysts; the synthetic route of 2-nitro-1,3-propanediol sodium salt as raw material, which uses flammable, explosive and highly toxic raw materials, and has a long synthetic route, serious "three wastes" pollution, and poor comprehensive benefits; the synthetic route of β-hydroxyamino acid or amino acid ester as raw material, although the yield is high, the raw materials are expensive and the cost is high. Therefore, it is inevitable to develop a low-cost and easy-to-operate process. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention provides a low-cost and easy-to-operate method for preparing serinol, which comprises the following steps:

[0005] Step 1: adding 3-halogenated propylene of formula I to ammonia water, adding peroxide, and reacting to generate 1,2-oxazetidine-3-carboxaldehyde of formula II;

[0006] Step 2: Hydrogenate and reduce the 1,2-oxazetidine-3-carboxaldehyde of formula II to open the ring and obtain serinol.

[0007] The synthesis path is as follows:

[0008]

[0009] In the formula, X is a halogenated group.

[0010] Preferably, the halogen X is Br or Cl.

[0011] Preferably, the peroxide is selected from: tert-butyl peroxide (TBHP), dibenzoyl peroxide (BPO), persulfate, meta-chloroperbenzoic acid (m-CPBA).

[0012] Preferably, in step 2, the hydrogenation reagent is lithium aluminum hydride or lithium borohydride.

[0013] The reaction of step 1 is carried out in an aqueous phase system at a reaction pressure of 5 to 10 MPa, preferably 10 MPa. The reaction temperature is initially 60 to 80°C for 0.5 to 1 day, and after the reaction, the temperature is lowered and the pressure is reduced, and the product of step 1 is obtained by column chromatography.

[0014] The reaction in step 2 is carried out in an organic solvent, and commonly used solvents are tetrahydrofuran, toluene, ethyl acetate, etc. The reaction temperature is 50-70°C and the reaction time is 5-7h. After the reaction is completed, hydrochloric acid solution is added to invert the phase, and the crude product is extracted with ethyl acetate, dried, filtered, and then refined.

[0015] The present invention further provides an intermediate for synthesizing serinol, which has a structure of formula II.

[0016] After repeated studies, the inventors selected the common 3-halopropylene as the raw material, cleverly utilized oxidation to form a ring and then reduction to open the ring, and prepared a new intermediate, namely 1,2-oxazetidine-3-carboxaldehyde of formula II, to simply and efficiently prepare serinol, and the product purity meets the requirements of industrial application.

[0017] In step 1 of the present invention, the peroxide is both an oxygen donor and a strong reducing agent, and the prepared 1,2-oxazetidine-3-carboxaldehyde of formula II can be hydrogenated and reduced to open the ring in one step to obtain the final product serinol. DETAILED DESCRIPTION

[0018] In order to understand the present invention more clearly, we further illustrate it in conjunction with reaction examples.

[0019] Unless otherwise stated, all materials, solvents and reagents, including inorganic solutions such as hydrochloric acid (10%), organic solvents such as tetrahydrofuran, toluene, ethyl acetate, etc., were of the best grade obtained from commercial suppliers without further purification.

[0020] 1 H(400MHz) and 13 C NMR (100 MHz) data were obtained using CDCl 3 The chemical shifts (δ) were given in ppm and the coupling constants (J) were given in Hz as solvents on a Bruker AVANCE II 400 MHz. 1 H NMR spectra were recorded using tetramethylsilane (δ = 0.00 ppm) as internal reference; 13 CNMR spectroscopy with CDCl 3 (δ=77.00 ppm) or DMSO-D 6 (δ=39.5 ppm) was recorded as an internal reference.

[0021] Example 1: Reaction of step 1

[0022] Example 1-1: Preparation of 1,2-oxazetidine-3-carboxaldehyde

[0023] 7.65 g of 3-chloropropene, 100 g of ammonia water (25%), and 38.61 g of TBHP (70% aqueous solution) were added into a high-pressure reactor (10 MPa), and the temperature was slowly raised to 70°C and kept for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature; the feed liquid was taken out and placed in a water bath below 40°C to remove ammonia under reduced pressure, and the mixed liquid was subjected to column chromatography to obtain 7.4 g of a yellow oily substance with a yield of 85%.

[0024] Example 1-2: Preparation of 1,2-oxazetidine-3-carboxaldehyde

[0025] 12.1 g of 3-bromopropylene, 100 g of ammonia water (25%), and 484.48 g of dibenzoyl peroxide (BPO) (10% aqueous solution) were added into a high-pressure reactor (8 MPa), and the temperature was slowly raised to 65° C. and kept for reaction for 15 hours. After the reaction was completed, the temperature was lowered to room temperature; the feed liquid was taken out and placed in a water bath below 40° C. to remove ammonia under reduced pressure, and the mixed solution was subjected to column chromatography to obtain 7.02 g of a yellow oily substance with a yield of 80.6%.

[0026] Example 1-3: Preparation of 1,2-oxazetidine-3-carboxaldehyde

[0027] 7.65 g of 3-chloropropene, 100 g of ammonia water (25%), and 53.93 g of m-chloroperbenzoic acid (80% ethanol solution) were added into a high-pressure reactor (10 MPa) with stirring, and the temperature was slowly raised to 75°C and kept for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature; the feed liquid was taken out and placed in a water bath below 40°C to remove ammonia under reduced pressure, and the mixed liquid was subjected to column chromatography to obtain 6.1 g of a yellow oily substance with a yield of 70.1%.

[0028] Example 1-4: Preparation of 1,2-oxazetidine-3-carboxaldehyde

[0029] 12.1 g of 3-bromopropylene, 100 g of ammonia water (25%), and 59.53 g of sodium persulfate (80% aqueous solution) were added into a high-pressure reactor (8 MPa), and the temperature was slowly raised to 60° C. and kept for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature; the feed liquid was taken out and placed in a water bath below 40° C. to remove ammonia under reduced pressure, and the mixed liquid was subjected to column chromatography to obtain 6.5 g of a yellow oily substance with a yield of 74.6%.

[0030] The NMR data of the product 1,2-oxazetidine-3-carboxaldehyde in Example 1 are as follows:

[0031] 1 H NMR (400 MHz, CDCl 3 )δ9.72(d, 1 H),3.96-4.21(m, 2H),3.7(d, 1 H),3.49(m, 1 H).

[0032] 13 C NMR (100 MHz, CDCl 3 )δ65.5,73.1,200.1.

[0033] ESI-TOF-HRMS calculation C 3 H 5 NO 2 (M+Na) 87.0320 Molecular weight, found 87.0322.

[0034] Example 2: Reaction of step 2

[0035] Example 2-1: Preparation of serinol

[0036] Weigh 4.35g of 1,2-oxazetidine-3-carboxaldehyde prepared in Example 1, add it to a round-bottom flask, put in a magnetic rotor, add 80mL of dry tetrahydrofuran, stir evenly, add 5g of lithium aluminum hydride in batches at 0°C, slowly increase the temperature to 55°C, and react at a constant temperature for 4h until the raw material disappears completely. Then add 5mL of ethyl acetate, and then drop a 10% hydrochloric acid solution until no bubbles are generated, then extract with ethyl acetate, dry with anhydrous sodium sulfate, filter, and spin dry to obtain 4.21g of crude serinol.

[0037] Dissolve the crude serinol in 1.5 times the weight of isopropanol, heat to reflux and stir for 30 minutes, slowly cool to below 30°C, keep the stirring speed not too high, continue to stir slowly until solids slowly precipitate, continue to stir until a large amount of solids precipitate, then cool to 15°C, stir slowly for 30 minutes,

[0038] The mixture was taken out and filtered to obtain 3.7 g of serinol white crystals, with a yield of 81.2% and a melting point of 53°C.

[0039] Sampling and testing, purity is not less than 99.7%.

[0040] Example 2-2: Preparation of serinol

[0041] Except that the hydrogenation reagent was replaced with 2.8 g of lithium borohydride, other reaction conditions were the same as those in Example 2-1, and 4.05 g of crude serinol was obtained.

[0042] According to the purification method of Example 2-1, 3.5 g of serinol white crystals were obtained with a yield of 76.8% and a melting point of 53° C. After sampling and testing, the purity was not less than 99.6%.

[0043] The above shows and describes the specific implementation examples of the present invention and the advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention needs to be constantly changed and improved. These changes and improvements fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing serinol, the method comprising the following steps: Step 1: adding 3-halogenated propylene of formula I to ammonia water, adding peroxide, and reacting to generate 1,2-oxazetidine-3-carboxaldehyde of formula II; Step 2: Hydrogenate and reduce the 1,2-oxazetidine-3-carboxaldehyde of formula II to obtain serinol. In the formula, X is a halogenated group.

2. The preparation method according to claim 1, characterized in that The X is Br or Cl.

3. The preparation method according to claim 1, characterized in that: The peroxide is selected from any one of tert-butyl peroxide, dibenzoyl peroxide, persulfate and m-chloroperbenzoic acid.

4. The preparation method according to claim 1, characterized in that: In the step 2, the hydrogenation reagent is lithium aluminum hydride or lithium borohydride.

5. An intermediate compound for synthesizing serinol, which has the structure of formula II as described below:

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