CN111848423A - Preparation method of tert-butyl 3-oxocyclobutylcarbamate - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tert-butyl 3-oxocyclobutyl carbamate (I), which comprises the following steps: and protecting the compound IV to generate a compound III, performing Hofmann degradation reaction to obtain a compound II, and finally performing deprotection to obtain a compound I. Compared with the prior art, the method has the advantages of low cost of the technical route, mild reaction conditions, no use of toxic reagents with large risk coefficients, environmental protection and good application value.

Description

Preparation method of tert-butyl 3-oxocyclobutylcarbamate

The technical field is as follows:

the invention belongs to the technical field of medicines, and particularly relates to a preparation method of tert-butyl 3-oxocyclobutylcarbamate.

Background art:

aminocyclobutane, as an important molecular scaffold, is widely used in the design of new drug molecules, such as drugs for treating hepatitis c virus infection (WO 2013064538); LSD1 inhibitors containing an aminocyclobutane skeleton (WO 2013057322); aminocyclobutane-containing JAK and SYK inhibitors (WO 2013030138); 1, 3-cyclobutanediamine containing aminocyclobutane (CN 104829492); aminocyclobutane containing elvan intermediate (WO2015010297, WO2013107291 and WO 2013107405). And tert-butyl 3-oxocyclobutylcarbamate (CAS number: 154748-49-9) having an aminocyclobutane structure is an important intermediate for synthesizing such compounds. There are several publications reporting the synthesis of tert-butyl 3-oxocyclobutylcarbamate.

Patents WO2015010297, WO2013107291 and WO2013107405 all disclose processes for the preparation of tert-butyl 3-oxocyclobutylcarbamate starting from 3-oxocyclobutanecarboxylic acid, the route being as in Scheme 1.

The 3-oxocyclobutanecarboxylic acid is used as a raw material, and tert-butyl 3-oxocyclobutyl carbamate is obtained through three reactions of chlorination, substitution and rearrangement. Column chromatography purification is used for a plurality of times in the reaction process, and NaN is used₃And the like, and is not suitable for industrial production.

Patent WO2017019589 discloses a process for preparing tert-butyl 3-oxocyclobutylcarbamate from 3-oxocyclobutanecarboxylic acid as a starting material, the route being shown in Scheme 2.

The 3-oxocyclobutanecarboxylic acid is used as a raw material in the route, although the 3-oxocyclobutanecarboxylic acid tert-butyl carbamate is obtained through one-step reaction, the yield is only 47%, and the requirement of industrial production cannot be met.

Patents WO2011044503, WO2010147836, WO2010132777 and the like disclose methods for preparing tert-butyl 3-oxocyclobutylcarbamate from 3-methylenecyclobutylcarbonitrile as a raw material, and routes are shown in Scheme 3.

The 3-oxocyclobutylcarbamic acid tert-butyl ester is obtained by using 3-methylenecyclobutylnitrile as a raw material through three-step reaction in the route, the yield is extremely low and is only 25%, and NaN is used ₃And the like, and is not suitable for industrial production.

The invention content is as follows:

in order to overcome the defects in the prior art, the invention discloses a preparation method of tert-butyl 3-oxocyclobutylcarbamate.

The specific process route is as follows:

wherein R is halogen substituted or unsubstituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted benzyl, or benzyl substituted with halogen.

In order to achieve the purpose, the invention adopts the following technical scheme:

step a): the compound IV is protected to generate a compound III,

step b): carrying out Hoffman degradation reaction on the compound III to obtain a compound II,

step c): deprotection of compound II produces compound I.

Further, R in the scheme is methyl or ethyl, preferably ethyl.

Further, the compound IV in step a) is reacted with trimethyl orthoformate or triethyl orthoformate to give compound III, preferably triethyl orthoformate.

Further, the reaction of step a) is carried out under the action of a catalyst selected from sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, preferably p-toluenesulfonic acid.

Further, an oxidant is used in the Hofmann degradation reaction in the step b), and the oxidant is selected from NaClO, NaBrO and Br ₂NaOH, preferably NaClO.

Further, the hofmann degradation reaction of step b) is carried out in an organic solvent selected from tetrahydrofuran, dichloromethane, 1, 4-dioxane, preferably tetrahydrofuran.

Further, the deprotection reaction in the step c) is carried out under the condition of an acid catalyst, and the acid catalyst is selected from hydrochloric acid and sulfuric acid.

Further, the acid concentration in the deprotection reaction of step c) is selected from 0.1 to 1mol/L, preferably 0.5 to 1 mol/L.

Compared with the prior art, the method has the advantages of low cost of the used technical route, mild reaction conditions, no use of toxic reagents with large risk coefficients, environmental friendliness, high yield and suitability for industrial production.

Drawings

Process for preparation of compound III of FIG. 1¹HNMR picture

FIG. 2 Process for preparation of Compound II¹HNMR picture

FIG. 3 Process for preparation of Compound I¹HNMR picture

Detailed Description

The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.

EXAMPLE 1 preparation of Compound III

Adding 50g of compound IV into 200mL of ethanol, then adding 3.8g of p-toluenesulfonic acid, cooling to 0-5 ℃, dropwise adding 79g of triethyl orthoformate, reacting at room temperature for 20h after completing dropwise adding, and tracking by TLC until the reaction is completed. Extracting with dichloromethane, concentrating to dryness, adding 50mL methyl tert-butyl ether, pulping, filtering, washing, and oven drying to obtain white solid 75g, with yield 91% and purity 98%. ¹The H NMR data are shown in FIG. 1.

EXAMPLE 2 preparation of Compound III

Adding 50g of compound IV into 200mL of ethanol, then adding 2.2g of concentrated sulfuric acid, cooling to 0-5 ℃, dropwise adding 79g of triethyl orthoformate, reacting at room temperature for 20h after the dropwise adding is finished, and tracking by TLC until the reaction is finished. Extracting with dichloromethane, concentrating to dryness, adding 50mL methyl tert-butyl ether, pulping, filtering, washing, and oven drying to obtain white solid 71g, with yield of 86% and purity of 98%.

EXAMPLE 3 preparation of Compound III

Adding 50g of compound IV into 200mL of methanol, then adding 3.8g of p-toluenesulfonic acid, cooling to 0-5 ℃, slowly dripping 57g of trimethyl orthoformate, reacting at room temperature for 20h after dripping, and tracking by TLC until the reaction is finished. Extracting with dichloromethane, concentrating to dryness, adding 50mL methyl tert-butyl ether, pulping, filtering, washing, and oven drying to obtain 62g white solid with yield of 88% and purity of 98%.

EXAMPLE 4 preparation of Compound III

Adding 50g of compound IV into 200mL of ethanol, then adding 2.2g of concentrated sulfuric acid, cooling to 0-5 ℃, dropwise adding 100g of tripropylorthoformate, reacting at room temperature for 20h after the dropwise addition is finished, and tracking by TLC until the reaction is finished. Extracting with dichloromethane, concentrating to dryness, adding 50mL methyl tert-butyl ether, pulping, filtering, washing, and drying to obtain 57g white solid.

EXAMPLE 5 preparation of Compound III

Adding 50g of compound IV into 200mL of ethanol, then adding 2.2g of concentrated sulfuric acid, cooling to 0-5 ℃, dropwise adding 123g of tributyl orthoformate, reacting at room temperature for 20h after the dropwise adding is finished, and tracking by TLC until the reaction is finished. Extracting with dichloromethane, concentrating to dryness, adding 50mL methyl tert-butyl ether, pulping, filtering, washing, and drying to obtain 62g of white solid.

EXAMPLE 6 preparation of Compound II

50g of the compound III obtained in example 1 was added to 200mL of tetrahydrofuran, cooled to 0 ℃, and then 21g of sodium hydroxide was dissolved in 240g of a sodium hypochlorite (10%) solution and added dropwise to the reaction system. And (3) carrying out reaction at 0-5 ℃, tracking by TLC until the reaction is finished, then adding 58g of di-tert-butyl dicarbonate, tracking by TLC until the reaction is finished, extracting by using dichloromethane, concentrating to dryness to obtain 66g of a crude product of the compound II, and directly using the crude product in the next step.¹The H NMR data are shown in FIG. 2.

EXAMPLE 7 preparation of Compound II

50g of the compound III obtained in example 3 was added to 200mL of tetrahydrofuran, cooled to 0 ℃ and then 21g of sodium hydroxide was dissolved in 384g of a sodium hypobromite (10%) solution and added dropwise to the reaction system. And (3) reacting at 0-5 ℃, tracking by TLC until the reaction is finished, adding 58g of di-tert-butyl dicarbonate, tracking by TLC until the reaction is finished, extracting by using dichloromethane, and concentrating to dryness to obtain 63g of a crude product of the compound II, wherein the crude product is directly used in the next step.

EXAMPLE 8 preparation of Compound I

66g of the compound II prepared in example 6 were added to 120mL of tetrahydrofuran, and then 120mL of 0.5mol/L dilute sulfuric acid was added, stirred at room temperature for 20 hours, concentrated to remove tetrahydrofuran, cooled, filtered, washed, and dried to obtain 43g of a white solid, yield 87% (total of two steps), and purity 99%.¹The H NMR data are shown in FIG. 3.

EXAMPLE 9 preparation of Compound I

63g of the compound II prepared in example 7 was added to 120mL of tetrahydrofuran, 120mL of 1mol/L diluted hydrochloric acid was added, the mixture was stirred at room temperature for 20 hours, the tetrahydrofuran was removed by concentration, and the mixture was cooled, filtered, washed and dried to obtain 47g of a white solid, yield 81% (total of the two steps) and purity 99%.

Claims (8)

1. A process for the preparation of the compound tert-butyl 3-oxocyclobutylcarbamate (compound I), comprising the steps of:

step a): the compound IV is protected to generate a compound III,

step b): carrying out Hoffman degradation reaction on the compound III to obtain a compound II,

step c): deprotecting compound II to produce compound I;

the specific route is as follows:

wherein R is halogen substituted or unsubstituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted benzyl, or benzyl substituted with halogen.

2. The method of claim 1, wherein: reacting the compound IV in the step a) with trimethyl orthoformate or triethyl orthoformate to obtain a compound III.

3. The method of claim 1, wherein: step a) is carried out under the action of a catalyst selected from sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid and acetic acid.

4. The method of claim 1, wherein: using an oxidant in the Hofmann degradation reaction in the step b), wherein the oxidant is selected from NaClO, NaBrO and Br₂/NaOH。

5. The method of claim 1, wherein: the Hofmann degradation reaction in the step b) is carried out in an organic solvent, wherein the organic solvent is selected from tetrahydrofuran, dichloromethane and 1, 4-dioxane.

6. The method of claim 1, wherein: and c) carrying out deprotection reaction under the condition of an acid catalyst, wherein the acid catalyst is selected from hydrochloric acid and sulfuric acid.

7. The method of claim 1, wherein: the concentration of the acid in the deprotection reaction in the step c) is selected from 0.1-1 mol/L.

8. A compound shown as a formula III is used for preparing 3-oxocyclobutylcarbamic acid tert-butyl ester.

Wherein R is halogen substituted or unsubstituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted benzyl, or benzyl substituted with halogen.

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