A process for the one-step synthesis of (r)-(-)-1,3-butanediol from diacetylene

Abstract

The application discloses a method for synthesizing (R)-( - )-1,3-butanediol by a one-step method of diketene, which uses a chiral ruthenium complex as a catalyst and a Bronsted acid as an assistant to make the diketene react by a one-step method under certain temperature and hydrogen pressure conditions to obtain (R)-( - )-1,3-butanediol. The method solves the problems of high cost, large catalyst consumption and difficult product separation in the prior art for preparing (R)-( - )-1,3-butanediol, and can asymmetrically hydrogenate the carbonyl group of the substrate diketene at low cost and with a small amount of catalyst, simultaneously reduces the ester group and opens the ring to obtain (R)-( - )-1,3-butanediol. The method has simple reaction operation and simple catalyst preparation, the yield of the target product and ee value are both above 98%, meanwhile, the catalyst can be repeatedly used, the cost is greatly reduced, and the method has the potential for industrial application.

Description

Technical Field

[0001] This invention relates to a synthetic method, and more particularly to a one-step method for synthesizing (R)-(-)-1,3-butanediol from diketene. Background Technology

[0002] (R)-(-)-1,3-Butanediol is an important chiral building block widely used in the synthesis of carbapenem antibiotics, nitrogen-containing heterocyclic methyl ethyl ketones, fragrances, pheromones, and insecticides. Since carbapenem antibiotics can effectively alleviate penicillin resistance, the synthesis of (R)-(-)-1,3-Butanediol has attracted widespread attention both domestically and internationally. Synthetic methods include chemical and microbiological approaches.

[0003] (R)-(-)-1,3-butanediol can be synthesized chemically by directly resolving racemic 1,3-butanediol. For example, Daicel Chemical in Japan reported that racemic 1,3-butanediol was prepared from acetaldehyde via aldol condensation and hydrogenation, and then resolved with a chiral resolving agent to obtain (R)-(-)-1,3-butanediol and (S)-(-)-1,3-butanediol. This method results in a loss of 50% of 1,3-butanediol, making it economically unsound. The literature Synth. Commun. 1991, 21(22): 2295-2300 reported the preparation of (R)-(-)-1,3-butanediol from L-threonine via a four-step reaction involving deamination, methylation, hydrodebromination, and reduction. This process has high material costs, generates a lot of waste, and the yield of the four-step reaction is only 64%. Another chemical synthesis method for preparing (R)-(-)-1,3-butanediol uses 4-hydroxy-2-butanone as a starting material and undergoes asymmetric hydrogenation. Numerous literature and patents have reported on the asymmetric hydrogenation of ketone carbonyl groups. For example, Noyori's Ru-BINAP catalytic system has been widely applied in the field of asymmetric catalysis of ketones, achieving an ee value (optical purity) of up to 99% for the target alcohol. However, these reports all use a metallic Ru catalytic system, which requires a large amount of catalyst that cannot be recovered, resulting in high costs. Furthermore, the industrial synthesis of 4-hydroxy-2-butanone involves the condensation reaction of formaldehyde and acetone, with a yield of only 70-80%. The separation and purification of 4-hydroxy-2-butanone is also difficult. Therefore, the overall cost of preparing (R)-(-)-1,3-butanediol via the asymmetric hydrogenation of 4-hydroxy-2-butanone is too high, making it unsuitable for industrial production.

[0004] One route for the microbial synthesis of (R)-(-)-1,3-butanediol uses racemic 1,3-butanediol as a starting material. For example, in the literature Biotechnol. Lett., 1993, 15(9):955-960, the two hydroxyl groups of racemic 1,3-butanediol are acylated by lipase SP382 (Candida sp.) to obtain (R)-1,3-diacetoxybutane, and then (R)-(-)-1,3-butanediol is obtained by chemical hydrolysis. The ee value can reach up to 98%, but the steps are long and the overall yield is low. Another route involves the asymmetric reduction of 4-hydroxy-2-butanone to (R)-(-)-1,3-butanediol using carbonyl reductases. For example, patents CN101899495 and CN109749968 report different strains used to catalyze the asymmetric reduction of 4-hydroxy-2-butanone to (R)-(-)-1,3-butanediol, achieving ee values ​​exceeding 99%. However, the disadvantages of microbial synthesis of (R)-(-)-1,3-butanediol are also obvious: long reaction times, low substrate concentrations leading to low space-time yields, and difficulties in product separation and purification, making industrial application challenging.

[0005] In summary, the chemical and microbial methods for preparing (R)-(-)-1,3-butanediol reported in current patent literature have drawbacks such as poor economic efficiency and difficulty in product separation. Therefore, developing new methods for synthesizing (R)-(-)-1,3-butanediol is of great significance. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention proposes a one-step method for synthesizing (R)-(-)-1,3-butanediol from diketene. This method overcomes the drawbacks of existing techniques for preparing (R)-(-)-1,3-butanediol, such as high cost, large catalyst usage, and difficult product separation. It enables the asymmetric hydrogenation of the carbonyl group of diketene with low cost and small catalyst usage, simultaneously reducing and ring-opening the ester group to obtain (R)-(-)-1,3-butanediol. This method features simple reaction operation, easy catalyst preparation, and target product yields and ee values ​​exceeding 98%. Furthermore, the catalyst can be reused multiple times, significantly reducing costs and demonstrating potential for industrial application.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] A method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene is disclosed, using a chiral ruthenium complex as a catalyst and Brønsted acid as an auxiliary agent. Under certain temperature and hydrogen pressure conditions, diketene is reacted in one step to obtain (R)-(-)-1,3-butanediol.

[0009] The possible reaction mechanism speculated from the above reactions is:

[0010]

[0011] As a preferred embodiment of the present invention, the chiral ruthenium complex is prepared in situ from a ruthenium metal precursor and a chiral tridentate P,N,N ligand; when preparing the chiral ruthenium complex, the molar ratio of the ruthenium metal precursor to the ligand is, for example, 1:(1-2), preferably 1:(1-1.2).

[0012] As a preferred embodiment of the present invention, the ruthenium metal precursor is one or more of RuCl3, RuI3, Ru(acac)3, and Ru(COD)Cl2, with RuCl3 being preferred.

[0013] As a preferred embodiment of the present invention, the amount of the chiral ruthenium complex is (0.00001-0.00006):1, calculated as the molar ratio of ruthenium to diketene in the ruthenium metal precursor.

[0014] As a preferred embodiment of the present invention, the ligand is selected from substances having the following structural formula:

[0015]

[0016] In Formula I, R1 and R2 are each independently a halogen, and are C1-C6 alkyl, alkoxy, or fluoroalkyl.

[0017] The ligands described in this invention are not limited in their source; they can be purchased from commercially available finished products or synthesized on a custom basis. As one feasible source of raw materials, a simple synthesis can be performed using the following methods:

[0018] The ligand described in Formula I was prepared by reacting compounds of Formula II, Formula III, phosphorus trichloride, and metallic magnesium as raw materials.

[0019]

[0020] Among them, R1 and R2 are each independently halogens, C1-C6 alkyl, alkoxy, and fluoroalkyl.

[0021] The molar ratio of the compound of formula II, the compound of formula III, and phosphorus trichloride is 2:(0.8-1.2):(1.0-1.5), preferably 2:(0.9-1):(1.1-1.2).

[0022] The molar ratio of metallic magnesium to phosphorus trichloride is 1:3.0-3.5, preferably 1:3.1-3.3.

[0023] As a preferred embodiment of the present invention, the ligand is selected from substances represented by the following structural formulas:

[0024]

[0025] More preferably, the ligand is a substance represented by the following structural formula:

[0026]

[0027] As a preferred embodiment of the present invention, the Brønsted acid is selected from one or more of diphenyl phosphate, di(2-ethylhexyl) phosphate, methyl phosphate, and ethyl phosphate.

[0028] As a preferred embodiment of the present invention, the amount of Brønsted acid used is 0.01-0.1% of the molar amount of diketene.

[0029] As a preferred embodiment of the present invention, the reaction temperature is 80-150℃, preferably 100-120℃; the hydrogen pressure is 6-12MPa, preferably 8-10MPa.

[0030] As a preferred embodiment of the present invention, the diketene has a purity of 99.0-99.9%, an oxygen content of less than 10 ppb, and a water content of less than 10 ppm.

[0031] The present invention, by adopting the above technical solution, has the following positive effects:

[0032] (1) This invention uses diketene as a raw material to synthesize (R)-(-)-1,3-butanediol, and proposes a new approach to the preparation of (R)-(-)-1,3-butanediol. The process is simple, the raw materials are cheap and readily available, and the yield and ee value of the product (R)-(-)-1,3-butanediol are both above 98%.

[0033] (2) Using a relatively inexpensive ruthenium complex catalyst, the carbonyl asymmetric hydrogenation and ester reduction of diketene can be completed simultaneously in one step, resulting in high product yield, good catalyst recyclability, and greatly reduced cost. Detailed Implementation

[0034] The present invention will be further illustrated below with specific embodiments. These embodiments are merely illustrative and do not limit the scope of the invention.

[0035] Unless otherwise specified, all raw materials used in the following embodiments of the present invention can be purchased commercially.

[0036] The main testing methods used in the following embodiments of the present invention are as follows:

[0037] The gas chromatography test conditions of this invention are as follows:

[0038] Instrument model: Agilent 7890B; Column: DB-3 capillary column (40m x 0.30mm x 0.25μm); Initial temperature 50℃, increased to 110℃ at a rate of 10℃ / min; then increased to 180℃ at a rate of 5℃ / min and held for 9 min. Carrier gas high...

[0039] Pure nitrogen, split ratio 40:1, split flow rate 45 mL / min. Carrier gas saving: 20 mL / min, start-up waiting time 2 min. Injection temperature 280℃, FID detector, detector temperature 280℃, air flow rate 350 mL / min, hydrogen flow rate 35 mL / min, make-up gas flow rate 30 mL / min, injection volume 0.2 μL.

[0040]

Preparation of Example 1

[0041] In a glove box, (R)-2-chloro-4-phenyl-oxazoline (0.41 g, 2.1 mmol), 2,6-dimethylbromobenzene (0.19 g, 1.01 mmol), and magnesium (0.07 g, 3.2 mmol) were added to a 50 mL Schlenk flask, with anhydrous tetrahydrofuran as the solvent, and the flask was sealed. After removing it from the glove box, the Schlenk flask was placed in a water bath, stirred, and heated under reflux for 1 h. Then, under a nitrogen atmosphere, phosphorus trichloride (0.13 g, 1 mmol) was added to the Schlenk flask, and the mixture was stirred at room temperature for 1 h. After the 2,6-dimethylbromobenzene reacted completely as monitored by TLC, the reaction was terminated, and an aqueous sodium bicarbonate solution was added to quench the reaction. The organic phase was extracted, and the alkali was recovered by vacuum distillation to obtain the crude product. The crude product was crystallized using a mixed solvent of dichloromethane and diethyl ether to obtain a product with a purity greater than 98%, denoted as ligand L1.

[0042]

[0043] 1 H NMR (400MHz, CDCl3): δ7.40-7.45(m,5H),7.25-7.29(m,6H),7.04(d,J=7.0Hz,2H),5.49(t,2H),4 .72(dd,J=10.4,5.8Hz,2H),4.47(dd,J=10.4,5.8Hz,2H),2.34(s,6H),1.40(s,2H),1.38(s,2H).

[0044]

Preparation of Example 2

[0045] The preparation was carried out in essentially the same manner as in Preparation Example 1, except that the starting material 2,6-dimethylbromobenzene was replaced with 1-bromo-2,6-dimethoxybenzene (0.22 g, 1.01 mmol). The prepared product was designated as ligand L2.

[0046]

[0047] 1 H NMR (400MHz, CDCl3): δ7.42-7.47(m,5H),7.26-7.31(m,6H),7.06(d,J=7.0Hz,2H),5.51(t,2H),4 .73(dd,J=10.4,5.8Hz,2H),4.49(dd,J=10.4,5.8Hz,2H),3.83(s,6H),1.43(s,2H),1.39(s,2H).

[0048] [Preparation Example 3]

[0049] The preparation was carried out in essentially the same manner as in Preparation Example 1, except that the starting material 2,6-dimethylbromobenzene was replaced with 1-bromo-2,6-difluorobenzene (0.19 g, 1.01 mmol). The prepared product was designated as ligand L3.

[0050]

[0051] 1 H NMR (400MHz, CDCl3): δ7.41-7.47(m,5H),7.24-7.31(m,6H),7.05(d,J=7.0Hz,2H),5.45(t ,2H),4.75(dd,J=10.4,5.8Hz,2H),4.45(dd,J=10.4,5.8Hz,2H),1.42(s,2H),1.36(s,2H).

[0052] [Preparation Example 4]

[0053] The preparation was carried out in essentially the same manner as in Preparation Example 1, except that the starting material 2,6-dimethylbromobenzene was replaced with 2,6-bis(trifluoromethyl)bromobenzene (0.29 g, 1.01 mmol). The prepared product was designated as ligand L4.

[0054]

[0055] 1H NMR (400MHz, CDCl3): δ7.42-7.48(m,5H),7.21-7.26(m,6H),7.02(d,J=7.0Hz,2H),5.47(t ,2H),4.70(dd,J=10.4,5.8Hz,2H),4.41(dd,J=10.4,5.8Hz,2H),1.44(s,2H),1.39(s,2H).

[0056]

Example 5

[0057] The preparation was carried out in essentially the same manner as in Preparation Example 1, except that the starting material 2,6-dimethylbromobenzene was replaced with bromobenzene (0.16 g, 1.01 mmol). The prepared product was designated as ligand L5.

[0058]

[0059] 1 H NMR (400MHz, CDCl3): δ7.45-7.49(m,9H),7.22-7.26(m,6H),5.45(t,2H),4.70( dd,J=10.4,5.8Hz,2H),4.43(dd,J=10.4,5.8Hz,2H),1.41(s,2H),1.35(s,2H).

[0060]

Example 1

[0061] In a glove box, RuCl3 (0.01 mmol), ligand L1 (0.012 mmol), and substrate diketene (84 g, 1 mol) were added to a single-necked flask equipped with a magnetic stirrer. Stirring was started, and after 30 minutes, the flask was sealed and removed from the glove box. Under nitrogen protection, the mixture was pumped into a 0.5 L reactor using a horizontal flow pump. The reactor had been pre-purged with nitrogen, and diphenyl phosphate (0.02% of the substrate molar weight) was added. After the mixture was added, the reactor was purged three times with hydrogen, and then charged with 5 MPa of hydrogen. Stirring and heating of the reactor were started. When the reactor temperature reached 80°C, the hydrogen inlet valve was opened, maintaining the reactor pressure at 6 MPa. Timing was started, and the reaction was maintained at this temperature for 2-3 hours. The reaction was terminated when the flow meter showed a hydrogen absorption rate of less than 0.1 mL / min.

[0062]

Examples 2-7

[0063] The reaction was carried out in essentially the same manner as in Example 1, except that the reaction conditions for each example are shown in Table 1:

[0064] Table 1. Different reaction conditions in Examples 1-7

[0065]

[0066] The reaction solutions obtained in each example were sampled and the yield and ee value of (R)-1,3-butanediol were analyzed by GC. The test results are shown in Table 2.

[0067] Table 2. Test Results

[0068] Product yield / % Product ee value / % Example 1 82.5 86.2 Example 2 86.3 90.2 Example 3 95.5 98.2 Example 4 83.6 90.3 Example 5 89.5 95.2 Example 6 98.5 99.2 Example 7 70.2 80.2

[0069] In addition, the recycling performance of the catalyst after the reaction in Example 6 was tested according to the following method:

[0070] Connect the discharge valve of the reactor to a condenser using a silicone tube. The condenser is connected to one port of a three-necked flask, and the other port of the flask is connected to a hydrazine coolant, which is then connected to a diaphragm pump. Turn on the heating and stirring in the reactor, and simultaneously adjust the vacuum level. Distill off all of the product (R)-1,3-butanediol using vacuum distillation. Purge the reactor with nitrogen gas, and add diketene (84 g, 1 mol) under a nitrogen atmosphere for the next batch reaction. With all experimental conditions unchanged, the product yield was 98.3%, and the ee value was 99.1%.

[0071] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene, characterized in that, Using a chiral ruthenium complex as a catalyst and Brønsted acid as an auxiliary agent, diketene was reacted in a one-step manner to obtain (R)-(-)-1,3-butanediol under certain temperature and hydrogen pressure conditions. The chiral ruthenium complex is prepared in situ from a ruthenium metal precursor and a chiral tridentate P,N,N ligand; the ruthenium metal precursor is one or more of RuCl3, RuI3, Ru(acac)3, and Ru(COD)Cl2; The ligands are selected from substances having the following structural formulas: Equation I; In Formula I, R1 and R2 are each independently selected from halogens, C1-C6 alkyl, alkoxy, and fluoroalkyl groups; The Brønsted acid is selected from one or more of diphenyl phosphate, di(2-ethylhexyl) phosphate, methyl phosphate, and ethyl phosphate.

2. The method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene according to claim 1, characterized in that, The amount of the chiral ruthenium complex used is (0.00001-0.00006):1, calculated as the molar ratio of ruthenium to diketene in the ruthenium metal precursor.

3. The method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene according to claim 1, characterized in that, The ligands are selected from substances represented by the following structural formulas: 。 4. The method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene according to claim 1, characterized in that, The amount of Brønsted acid used is 0.01-0.1% of the molar amount of diketene.

5. The method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene according to any one of claims 1-3, characterized in that, The reaction temperature is 80-150℃; the hydrogen pressure is 6-12 MPa.

6. The method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene according to claim 5, characterized in that, The reaction temperature is 100-120℃; the hydrogen pressure is 8-10 MPa.

7. The method for one-step synthesis of (R)-(-)-1,3-butanediol from diketene according to any one of claims 1-3, characterized in that, The diketene has a purity of 99.0-99.9%, an oxygen content of less than 10 ppb, and a water content of less than 10 ppm.

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