Preparation method for cheap synthesis of N-tert-butyloxycarbonyl-2-aminoacetaldehyde

Abstract

The invention discloses a cheap preparation method for synthesizing N-tert-butyloxycarbonyl-2-aminoacetaldehyde, which comprises the following steps: adding 3-amino-1, 2-propylene glycol and methanol / dichloromethane into a reaction kettle, adding Boc2O in an ice bath, reacting at room temperature, then adding a saturated salt solution, rotating out methanol, extracting a water phase by using dichloromethane, filtering, and drying to obtain the N-tert-butyloxycarbonyl-2-aminoacetaldehyde. And dissolving the intermediate I in water, adding sodium periodate in batches at the temperature of 10 DEG C, reacting at room temperature, filtering, extracting a water phase with dichloromethane, combining the organic phases, backwashing with the saturated saline solution, and drying and spin-drying to obtain a final product. The total yield of the product N-tert-butyloxycarbonyl-2-aminoacetaldehyde is not lower than 60%, and the purity of the product N-tert-butyloxycarbonyl-2-aminoacetaldehyde is not lower than 99.1%. Compared with the prior art, the process is simple, raw materials are cheap, the product purity is high, and the risk of excessive oxidation is avoided.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and mainly relates to the synthesis of N-tert-butyloxycarbonyl-2-aminoacetaldehyde, an intermediate of heterocyclic compounds, organic amines and tissue protease inhibitors. Background Art

[0002] N-tert-Butyloxycarbonyl-2-aminoacetaldehyde is an important intermediate for the synthesis of organic amines, heterocyclic compounds and tissue protease inhibitors. The early synthesis and preparation method of N-tert-Butyloxycarbonyl-2-aminoacetaldehyde: ethanolamine is used as the raw material, and after Boc, Dess-Martin oxidation is used to obtain N-tert-Butyloxycarbonyl-2-aminoacetaldehyde. Although the ethanolamine raw material is cheap and easy to obtain, the Dess-Martin reagent is expensive, and oxidation will produce more impurities and require column purification to obtain the product, resulting in a yield of only 30% and a purity of only 95%, which makes the overall process cost high. Summary of the invention

[0003] The present invention aims at the shortcomings of the current production process and provides a method for preparing N-tert-butyloxycarbonyl-2-aminoacetaldehyde inexpensively. The present invention uses 3-amino-1,2-propylene glycol as a starting material, adds it to a reactor, adds a solvent, Boc2O, reacts at room temperature for 3 hours, and then extracts, dries, and spin-dries to obtain intermediate I; intermediate I and the solvent are added to the reactor, sodium periodate is added in batches under an ice bath, and N-tert-butyloxycarbonyl-2-aminoacetaldehyde is obtained by filtering, extracting, and drying. The specific process route is as follows:

[0004]

[0005] S1: 3-amino-1,2-propanediol was dissolved in methanol / dichloromethane and added to the reaction kettle, and Boc2O was added under ice bath, reacted at room temperature, and then saturated brine was added, part of methanol was spun out, the aqueous phase was extracted with dichloromethane, the organic phases were combined, backwashed with saturated brine, dried, and spun to obtain intermediate I;

[0006] S2: Intermediate I was dissolved in water, sodium periodate was added in batches at 10°C, reacted at room temperature, filtered, the aqueous phase was extracted with dichloromethane, the organic phases were combined, backwashed with saturated brine, dried and spin-dried to obtain the final product.

[0007] The solvent in step S1 is one of methanol, dichloromethane or a mixed solvent thereof, the amount of the solvent is 3-5 times the volume of 3-amino-1,2-propanediol, and the reaction temperature is 20-30°C.

[0008] The molar ratio of sodium periodate to intermediate I in step S2 is 1-1.5, and the reaction temperature is 20-30°C.

[0009] Beneficial effects of the present invention:

[0010] The invention uses 3-amino-1,2-propylene glycol as a raw material and synthesizes N-tert-butyloxycarbonyl-2-aminoacetaldehyde through two steps of Boc and sodium periodate oxidation. The raw material of the invention is cheap and easy to obtain, the operation is simple, the reaction is stable and mild, the cost is low, the two-step yield can reach more than 60%, the gas phase purity is more than 99.1%, the generation of by-products is reduced, the production cost is effectively controlled, and it is more conducive to industrialization. DETAILED DESCRIPTION

[0011] Implementation 1:

[0012] Synthesis of Intermediate Ⅰ

[0013] Add 100g 3-amino-1,2-propanediol and 300mL (volume ratio 5:1) of methanol and dichloromethane mixed solvent to a 500mL three-necked flask, add Boc2O (250g) dropwise below 15°C, and then react at 25°C for 3h. After TLC detection of the complete reaction of the raw materials, add 100mL of saturated brine, spin out the methanol, extract the aqueous phase twice with dichloromethane, combine the dichloromethane phases, backwash twice with saturated brine, dry the organic phase with sodium sulfate, spin dry to obtain intermediate I (200g), which is directly used in the next step.

[0014] Synthesis of Intermediate II

[0015] Add 200g of intermediate I to a 2L reaction bottle, add 1.6L of water, cool to below 10°C, add sodium periodate (249g) in batches, and then react at 25°C for 2h. TLC detection shows that the raw material has reacted completely, filter out the solid, add dichloromethane to the filtrate and extract twice, combine the organic phases, backwash twice with saturated brine, dry with sodium sulfate, and spin dry to obtain 105g of intermediate II, with a yield of 62% and a gas phase purity of 99.2%.

[0016] Implementation 2:

[0017] Synthesis of Intermediate Ⅰ

[0018] 100 g of 3-amino-1,2-propanediol and 300 mL of a mixed solvent of methanol and dichloromethane (volume ratio 5:1) were added to a 500 mL three-necked flask, and Boc2O (250 g) was added dropwise below 15°C, followed by reaction at 25°C for 3 h. After TLC detection of the complete reaction of the raw material, 100 mL of saturated brine was added, methanol was removed by spinning, the aqueous phase was extracted twice with dichloromethane, the dichloromethane phases were combined, backwashed twice with saturated brine, the organic phase was dried with sodium sulfate, and the intermediate I (201 g) was obtained by spinning and used directly in the next step.

[0019] Synthesis of Intermediate II

[0020] Add 201g of intermediate I to a 2L reaction bottle, add 1.6L of water, cool to below 10°C, add sodium periodate (250g) in batches, and then react at 25°C for 2h. TLC detection shows that the raw material has reacted completely, filter out the solid, add dichloromethane to the filtrate and extract twice, combine the organic phases, backwash twice with saturated brine, dry with sodium sulfate, and spin dry to obtain 110g of intermediate II, with a yield of 63% and a gas phase purity of 99.1%.

[0021] Implementation 3:

[0022] Synthesis of Intermediate Ⅰ

[0023] 1Kg of 3-amino-1,2-propanediol and 3L of a mixed solvent of methanol and dichloromethane (volume ratio 5:1) were added to a 30L reactor, and Boc2O (2.5Kg) was added dropwise below 15°C, followed by reaction at 25°C for 3h. After TLC detected that the raw material had reacted completely, 1L of saturated brine was added, methanol was removed by spinning, the aqueous phase was extracted twice with dichloromethane, the dichloromethane phases were combined, backwashed twice with saturated brine, the organic phase was dried with sodium sulfate, and the intermediate I (2Kg) was obtained by spinning and used directly in the next step.

[0024] Synthesis of Intermediate II

[0025] Add 2 kg of intermediate I to a 30 L reaction bottle, add 16 L of water, cool to below 10 ° C, add sodium periodate (2.49 kg) in batches, and then react at 25 ° C for 2 hours. TLC detection shows that the raw material reaction is complete, filter out the solid, add dichloromethane to the filtrate and extract twice, combine the organic phases, backwash twice with saturated brine, dry with sodium sulfate, and spin dry to obtain 1.08 kg of intermediate II, with a yield of 62% and a gas phase purity of 99.1%.

[0026] Implementation 4:

[0027] Synthesis of Intermediate Ⅰ

[0028] Add 100g 3-amino-1,2-propanediol and 300mL of a mixed solvent of dichloromethane and methanol (volume ratio 1:5) to a 500mL three-necked flask, add Boc2O (250g) dropwise below 15°C, and then react at 25°C for 3h. After TLC detection of the complete reaction of the raw material, add 100mL of saturated brine, spin out the methanol, extract the aqueous phase twice with dichloromethane, combine the dichloromethane phases, backwash twice with saturated brine, dry the organic phase with sodium sulfate, spin dry to obtain intermediate I (195g), which is directly used in the next step.

[0029] Synthesis of Intermediate II

[0030] Add 195g of intermediate I to a 2L reaction bottle, add 1.6L of water, cool to below 10°C, add sodium periodate (247g) in batches, and then react at 35°C for 2h. TLC detection shows that the raw material has reacted completely, filter out the solid, add dichloromethane to the filtrate and extract twice, combine the organic phases, backwash twice with saturated brine, dry with sodium sulfate, and spin dry to obtain 98g of intermediate II, with a yield of 56% and a gas phase purity of 95%.

[0031] Implementation 5:

[0032] Synthesis of Intermediate Ⅰ

[0033] In a 500mL three-necked flask, add 100g of 3-amino-1,2-propanediol and 300mL of a mixed solvent of dichloromethane and methanol (volume ratio 1:5), add Boc2O (250g) dropwise below 15°C, and then react at 25°C for 3h. TLC detected that the raw material reacted completely, added 100mL of saturated brine, and the methanol was spun out. The aqueous phase was extracted twice with dichloromethane, the dichloromethane phases were combined, backwashed twice with saturated brine, and the organic phase was dried with sodium sulfate, and the intermediate I (180g) was obtained by spin drying, which was directly used in the next step.

[0034] Synthesis of Intermediate II

[0035] Add 180g of intermediate I to a 2L reaction bottle, add 1.5L of water, cool to below 10°C, add sodium periodate (223g) in batches, and then react at 15°C for 4h. TLC detection shows that the raw material has reacted completely, filter out the solid, add dichloromethane to the filtrate and extract twice, combine the organic phases, backwash twice with saturated brine, dry with sodium sulfate, and spin dry to obtain 88g of intermediate II, with a yield of 50% and a gas phase purity of 97.0%.

[0036] Although the above describes the specific implementation methods of the present invention, it is not intended to limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without creative work are still within the scope of protection of the present invention.

Claims

1. A method for preparing N-tert-butyloxycarbonyl-2-aminoacetaldehyde inexpensively is as follows: S1: 3-amino-1,2-propanediol, methanol / dichloromethane are added to the reaction kettle, Boc2O is added under ice bath, reacted at room temperature, then saturated brine is added, methanol is spun out, the aqueous phase is extracted with dichloromethane, the organic phases are combined and backwashed with saturated brine, dried, and spun to obtain intermediate Ⅰ; S2: Intermediate I was dissolved in water, sodium periodate was added in batches at 10°C, reacted at room temperature, filtered, the aqueous phase was extracted with dichloromethane, the organic phases were combined, backwashed with saturated brine, dried and spin-dried to obtain the final product.

2. The method for preparing N-tert-butyloxycarbonyl-2-aminoacetaldehyde according to claim 1, characterized in that: In step S1, the reaction solvent is methanol, dichloromethane or a mixed solvent thereof, and the amount of the solvent is 3-5 times the volume of 3-amino-1,2-propanediol.

3. The method for preparing N-tert-butyloxycarbonyl-2-aminoacetaldehyde according to claim 1, characterized in that: The reaction temperature in step S1 is 20-30°C.

4. The method for preparing N-tert-butyloxycarbonyl-2-aminoacetaldehyde according to claim 1, characterized in that: The molar ratio of sodium periodate to intermediate I in step S2 is 1-1.

5.

5. The method for preparing N-tert-butyloxycarbonyl-2-aminoacetaldehyde according to claim 1, characterized in that: The reaction temperature in step S2 is 20-30°C.

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