Synthesis method of (R)-3-amino-1-butanol

Abstract

The invention belongs to the field of pharmaceutical and chemical industry, and particularly relates to a production method of a chiral drug intermediate (R)-3-amino-1-butanol. According to the production method of the chiral drug intermediate (R)-3-amino-1-butanol, (R)-3-aminobutyric acid is adopted as a raw material, and through four basic steps of esterification, amino protection, reduction anddeprotection, a product with excellent chemical purity and excellent optical purity is obtained. According to the production method of the chiral drug intermediate (R)-3-amino-1-butanol, the adoptedraw material is easy to obtain and cheap, compared with existing chemical resolution and chiral introduction, the production method of the chiral drug intermediate (R)-3-amino-1-butanol has the advantages that the yield is greatly improved, the cost is reduced, and large-scale production is easy to achieve, so that the production method of the chiral drug intermediate (R)-3-amino-1-butanol is a synthesis method with low safety risks and multiple advantages.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a chiral drug intermediate (R)-3-aminobutanol. Background technique

[0002] (R)-3-aminobutanol, (R)-3-amino-1-butanol, CAS: 61477-40-5, colorless or light yellow liquid, easily soluble in tetrahydrofuran, ethanol, water and other solvents, is a lot Key intermediates of chiral drugs. Such as J.Org.Chem., 1977, 42:1650, it is reported that it is the key intermediate of antineoplastic drug 4-methyl cyclophosphamide; Tetrahed.Lett., 1988,29:231, it is reported that it is a synthetic penem An important intermediate of antibiotics; Drugs.Of the Future 2012,37:697, it is reported that it is a key intermediate for the synthesis of the chiral six-membered ring of the anti-AIDS drug dolutegravir.

[0003] (R)-3-aminobutanol structural formula is shown in following formula (A):

[0004]

[0005] There are many synthetic patent reports ...

Examples

Embodiment 1

[0043] Embodiment 1: the synthesis of (R)-3-aminobutyric acid methyl ester

[0044] Put 240g of methanol and 50g of (R)-3-aminobutyric acid into the clean reaction flask, cool with ice water, the temperature drops to 0-10°C, and slowly add 66.4g of thionyl chloride dropwise. After the dropwise addition, the temperature was raised to reflux until the raw materials disappeared. The reaction solution was directly concentrated under reduced pressure to obtain the product. Yield: 98.5%, purity: 99.7%, ee: 99.9%.

Embodiment 2

[0045] Embodiment 2: the synthesis of (R)-3-benzyloxyamidobutyric acid methyl ester

[0046] Put 50g of (R)-3-aminobutyric acid methyl ester hydrochloride, 400g of water into the clean four-neck bottle, and slowly put in 41.4g of sodium carbonate. After feeding, stir to dissolve, the temperature drops to 0-10°C, slowly add 55.5g of benzyl chloroformate dropwise, and control the temperature at 0-10°C. After the dropwise addition, raise the temperature to 20-30°C, keep stirring for 3-4 hours until the raw materials disappear. The reaction liquid was extracted by adding 200ML*2 times of dichloromethane, and the layers were separated. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the product. Yield: 95.3%, purity 99.4%, ee: 99.9%.

[0047] HNMR (400MH Z ,DMSO-D 6 ):δ1.086~1.099(d,3H),δ2.367~2.411(m,1H),δ2.488~2.532(m,1H),δ3.576(s,3H),δ3.886~3.914( m, 1H), δ5.012(s, 2H), δ7.273~7.387(m, 5H).; NMR spectrum as fig...

Embodiment 3

[0048] Embodiment 3: the synthesis of (R)-3-benzyloxy amidobutanol

[0049] Put 50g of (R)-3-benzyloxyamidobutanoic acid methyl ester and 250ML of ethanol into a clean four-necked bottle, and stir to dissolve. When the temperature dropped to 0-10°C, 16.6g of potassium borohydride was added first, and then 45.7g of magnesium chloride was added, and kept stirring for 5 hours. After the raw material detection and reaction were completed, aqueous hydrochloric acid solution was added dropwise to quench. After filtration, the filtrate was concentrated under reduced pressure until there was no distillate, and white crystals were obtained by crystallization. Yield: 94.2%, purity: 99.2%, ee: 99.9%.

[0050] HNMR (400MH Z ,DMSO-D 6):,1.048~1.061(d,3H),δ1.487~1.607(m,2H),δ3.383~3.418(m,2H),δ3.624~3.651(m,1H),δ4.379~4.398 (t, 1H), δ5.010(s, 2H), δ7.099~7.388(m, 5H); figure 2 shown.

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a chiral drug intermediate (R)-3-aminobutanol. Background technique

[0002] (R)-3-aminobutanol, (R)-3-amino-1-butanol, CAS: 61477-40-5, colorless or light yellow liquid, easily soluble in tetrahydrofuran, ethanol, water and other solvents, is a lot Key intermediates of chiral drugs. Such as J.Org.Chem., 1977, 42:1650, it is reported that it is the key intermediate of antineoplastic drug 4-methyl cyclophosphamide; Tetrahed.Lett., 1988,29:231, it is reported that it is a synthetic penem An important intermediate of antibiotics; Drugs.Of the Future 2012,37:697, it is reported that it is a key intermediate for the synthesis of the chiral six-membered ring of the anti-AIDS drug dolutegravir.

[0003] (R)-3-aminobutanol structural formula is shown in following formula (A):

[0004]

[0005] There are many synthetic patent reports ...

Examples

Embodiment 1

[0043] Embodiment 1: the synthesis of (R)-3-aminobutyric acid methyl ester

[0044] Put 240g of methanol and 50g of (R)-3-aminobutyric acid into the clean reaction flask, cool with ice water, the temperature drops to 0-10°C, and slowly add 66.4g of thionyl chloride dropwise. After the dropwise addition, the temperature was raised to reflux until the raw materials disappeared. The reaction solution was directly concentrated under reduced pressure to obtain the product. Yield: 98.5%, purity: 99.7%, ee: 99.9%.

Embodiment 2

[0045] Embodiment 2: the synthesis of (R)-3-benzyloxyamidobutyric acid methyl ester

[0046] Put 50g of (R)-3-aminobutyric acid methyl ester hydrochloride, 400g of water into the clean four-neck bottle, and slowly put in 41.4g of sodium carbonate. After feeding, stir to dissolve, the temperature drops to 0-10°C, slowly add 55.5g of benzyl chloroformate dropwise, and control the temperature at 0-10°C. After the dropwise addition, raise the temperature to 20-30°C, keep stirring for 3-4 hours until the raw materials disappear. The reaction liquid was extracted by adding 200ML*2 times of dichloromethane, and the layers were separated. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the product. Yield: 95.3%, purity 99.4%, ee: 99.9%.

[0047] HNMR (400MH Z ,DMSO-D 6 ):δ1.086~1.099(d,3H),δ2.367~2.411(m,1H),δ2.488~2.532(m,1H),δ3.576(s,3H),δ3.886~3.914( m, 1H), δ5.012(s, 2H), δ7.273~7.387(m, 5H).; NMR spectrum as fig...

Embodiment 3

[0048] Embodiment 3: the synthesis of (R)-3-benzyloxy amidobutanol

[0049] Put 50g of (R)-3-benzyloxyamidobutanoic acid methyl ester and 250ML of ethanol into a clean four-necked bottle, and stir to dissolve. When the temperature dropped to 0-10°C, 16.6g of potassium borohydride was added first, and then 45.7g of magnesium chloride was added, and kept stirring for 5 hours. After the raw material detection and reaction were completed, aqueous hydrochloric acid solution was added dropwise to quench. After filtration, the filtrate was concentrated under reduced pressure until there was no distillate, and white crystals were obtained by crystallization. Yield: 94.2%, purity: 99.2%, ee: 99.9%.

[0050] HNMR (400MH Z ,DMSO-D 6):,1.048~1.061(d,3H),δ1.487~1.607(m,2H),δ3.383~3.418(m,2H),δ3.624~3.651(m,1H),δ4.379~4.398 (t, 1H), δ5.010(s, 2H), δ7.099~7.388(m, 5H); figure 2 shown.

Images