CN109096098B - Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid - Google Patents
Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid Download PDFInfo
- Publication number
- CN109096098B CN109096098B CN201811007287.5A CN201811007287A CN109096098B CN 109096098 B CN109096098 B CN 109096098B CN 201811007287 A CN201811007287 A CN 201811007287A CN 109096098 B CN109096098 B CN 109096098B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparing
- reaction
- preparation
- molar ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
- C07C67/22—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of trans-1, 3-dihydroxy-cyclobutane-1-carboxylic acid, which mainly solves the technical problem of lack of a synthesis process of the trans-1, 3-dihydroxy-cyclobutane-1-carboxylic acid and comprises the following steps: taking a compound II (3- (benzyloxy) -1-cyclobutanone) as a raw material, and reacting with trimethylsilyl cyanide to generate a compound III; carrying out alcoholysis on the cyano group of the compound III to generate a compound IV; then hydrolyzing to generate a compound V; recrystallizing and separating the compound V to obtain a cis-form compound VI; esterifying the compound VI to generate a compound VII; hydroxyl in the compound VII is protected by tert-butyldimethylsilyl chloride to generate a compound VIII; removing benzyl protecting group from the compound VIII to obtain a compound IX; carrying out Mitsunobu reaction on the compound IX and p-nitrobenzoic acid to generate a compound X, then removing p-nitrobenzoyl to obtain a compound XI, and overturning the hydroxyl configuration; finally hydrolyzing to obtain the compound I (trans-1, 3-dihydroxy cyclobutane-1-carboxylic acid).
Description
Technical Field
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of trans-1, 3-dihydroxy cyclobutane-1-carboxylic acid and an intermediate thereof.
Background
The 1-hydroxycyclobutane-1-carboxylic acid derivative is an important medical intermediate, can be used for synthesizing medicaments with thrombin inhibitor activity, and has very important function in medical synthesis. International publication WO1998011094A1 reports that 1, 3-dihydroxycyclobutane-1-carboxylic acid can be used to prepare benzamidine derivatives substituted with cyclic hydroxycarboxylic acid derivatives having anticoagulant utility. Generally, compounds with optical activity have wider application in drug design, and no literature report exists on the synthesis method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid at present. Therefore, it is necessary to develop a synthetic route with easily available raw materials, convenient operation, easy control of the reaction and proper overall yield.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a method for synthesizing trans-1, 3-dihydroxy cyclobutane-1-carboxylic acid, which mainly solves the technical blank of the existing preparation method. Provides a synthetic route which has the advantages of easily obtained raw materials, convenient operation, easy control of reaction and proper overall yield.
Taking a compound II (3- (benzyloxy) -1-cyclobutanone) as a raw material, and reacting with trimethylsilyl cyanide to generate a compound III; carrying out alcoholysis on the cyano group of the compound III to generate a compound IV; then hydrolyzing to generate a compound V; recrystallizing and separating the compound V to obtain a cis-form compound VI; esterifying the compound VI to generate a compound VII; hydroxyl in the compound VII is protected by tert-butyldimethylsilyl chloride to generate a compound VIII; removing benzyl protecting group from the compound VIII to obtain a compound IX; carrying out Mitsunobu reaction on the compound IX and p-nitrobenzoic acid to generate a compound X, then removing p-nitrobenzoyl to obtain a compound XI, and overturning the hydroxyl configuration; finally hydrolyzing to obtain the compound I (trans-1, 3-dihydroxy cyclobutane-1-carboxylic acid).
In one aspect, the invention provides a method for preparing a synthetic compound VI:
wherein: r1Is methyl or ethyl; when the compound V is used for preparing the compound VI, recrystallization treatment is needed;
preferably, in the step of preparing the compound III from the compound II, the molar ratio of the compound II to the trimethylsilyl cyanide is 1: 1-1: 2;
preferably, in the step of preparing the compound III from the compound II, the base 1 can be added in the reaction; the base 1 is selected from potassium carbonate, sodium carbonate or cesium carbonate; the molar ratio of the compound II, the trimethylsilyl cyanide and the alkali is 1: 1-2: 0.5-2;
preferably, in the step of preparing the compound IV from the compound III, the acid 1 is thionyl chloride or concentrated sulfuric acid; the alcohol 1 is methanol or ethanol; the molar ratio of the compound III to the acid is 1: 0.1-1: 3;
preferably, in the step of preparing compound V from compound IV, the base 2 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide;
preferably, in the step of preparing compound VI from compound V, the recrystallization solvent is dichloromethane/n-heptane, dichloromethane/petroleum ether, ethyl acetate/n-heptane or ethyl acetate/petroleum ether.
In another aspect, the invention provides a process for preparing compound I:
wherein: r1Is methyl or ethyl.
Preferably, in the step of preparing the compound VII by using the compound VI, the acid 2 is thionyl chloride or concentrated sulfuric acid; the alcohol 2 is methanol or ethanol; the molar ratio of the compound V to the acid 2 is 1: 0.1-1: 2;
preferably, in the step of preparing the compound VIII from the compound VII, the base 3 is selected from imidazole, triethylamine or N, N-diisopropylethylamine; the molar ratio of the compound VII, the tert-butyldimethylsilyl chloride and the alkali 3 is 1: 1.0-2.0; the reaction temperature range is 0-40 ℃;
preferably, in the step of preparing the compound X from the compound IX, the azo reagent is diisopropyl azodicarboxylate or diethyl azodicarboxylate; compounds IX, PPh3And the azo reagent in a molar ratio range of: 1: 0.9-2; the reaction temperature range is 10-60 ℃;
preferably, in the step of preparing compound XI from compound X, the base 4 is selected from potassium carbonate, cesium carbonate, sodium methoxide or sodium ethoxide; the molar ratio of the compound X to the alkali 4 is 1: 0.1-1: 1;
preferably, in the step of preparing the compound I by the compound XI, the base 5 is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide; the molar ratio of the compound XI to the alkali 5 is 1: 1-1: 2.
Advantageous effects
The invention provides a simple, convenient and effective synthetic route for the first time, the important drug intermediate 1, 3-dihydroxy cyclobutane-1-carboxylic acid with optical activity is obtained by synthesis, the technical blank of the preparation method of trans-1, 3-dihydroxy cyclobutane-1-carboxylic acid is made up, the reaction condition is mild, the operation is simple and convenient, and the rapid preparation in a laboratory can be realized.
Abbreviations for the reagents referred to in the specification are as follows:
TBSCl: tert-butyldimethylsilyl chloride;
the DIAD: diisopropyl azodicarboxylate;
DEAD: diethyl azodicarboxylate;
TEA: triethylamine;
DIPEA: n, N-diisopropylethylamine;
PE: petroleum ether;
THF: tetrahydrofuran;
DCM: dichloromethane;
MeOH: methanol;
EtOH: ethanol;
EA: ethyl acetate;
PPh3: triphenylphosphine.
Detailed Description
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of Compound III
Compound II (80.00g,0.454mol,1.0eq.) was dissolved in 600mL THF, K was added2CO3(75.32g, 0.545mol,1.2eq.) and TMSCN (54.05g,0.545mol,1.2eq.), reacted at 20 ℃ for 3h, the TLC detection reaction was complete, filtered, and the filtrate was concentrated to obtain 120.0g of compound III as a red liquid, with yield: 96.0 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C15H21NO2Si：275；found：276。
Preparation of Compound IV-1
Compound III (104.11g, 0.378mol, 1.0eq.) is dissolved in 500mL MeOH and SOCl is added dropwise under ice bath2(80.90g, 0.684mol, 1.8eq.), controlling the temperature to be lower than 35 ℃, after dripping, heating and refluxing at 55 ℃ for reaction for 3 hours, and generating a large amount of solid. And (5) detecting by TLC, and completing the reaction. Methanol was concentrated, 500mL of methyl tert-ether was added, filtration was carried out, the filtrate was washed with water, and after drying, concentration was carried out to obtain compound IV-1 as a brown liquid 80.0g, yield: 89.6 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C13H16O4：236；found：237。
Preparation of Compound V
Compound IV-1(40.0g, 0.169mol, 1.0eq.) was dissolved in 150mL MeOH, 30mL water was added, and sodium hydroxide (6.75g, 0.169mol, 1.0eq.) was added. The reaction is carried out for 4h at 20 ℃. TLC detected the reaction was complete, methanol was concentrated, 50mL of water was added, impurities were extracted with methyl tert-ether, pH was adjusted to 1 with 6N hydrochloric acid, extracted with methyl tert-ether, the organic phases were combined, washed with saturated brine, dried, concentrated and washed with N-heptane to give compound V as a white solid 32.1 g.
Preparation of Compound VI
Compound V (32.1g) was recrystallized from DCM/hexanes (2/1200 mL) to give compound VI as a white solid, 20.0g, two-step yield: 53.25 percent.1H-NMR(400MHz，CDCl3)δ(ppm)：7.36～7.28(m，5H)，4.49(s，1H)，4.12～4.06(m，1H)，2.94～2.89(m，2H)，2.43～2.38(m，2H)。
Preparation of Compound VII-1
VI (8.00g, 0.036mol, 1.0eq.) was dissolved in 30mL MeOH and SOCl was added dropwise2((6.42g, 0.054mol, 1.5eq.) dramaticThe mixture is discharged strongly and releases heat, and after dripping, the mixture reacts for 2 hours at the temperature of 20 ℃. And (3) detecting by LC-MS (liquid chromatography-mass spectrometry), completely reacting, concentrating the reaction solution, adding water and methyl tert-ether and sodium bicarbonate solid, stirring, separating, drying the organic phase, and concentrating to obtain 8.00g of a colorless liquid of the compound VII-1, wherein the yield is as follows: 94.1 percent.
Preparation of Compound VIII-1
Compound VII-1(8.00g, 0.034mol,1.0eq.) was dissolved in 60mL DCM, imidazole (3.00g, 0.044mol, 1.3eq.) was added, and TBSCl (6.12g, 0.04036mol, 1.2eq.) was added dropwise with ice bath, temperature was controlled below 20 ℃ and reaction was carried out at 40 ℃ for 16 h. TLC detection has a small amount of raw material residue, the reaction solution is added with 20mL of water and washed once, then washed once with 10mL of saturated salt, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated to obtain 13.0g of compound VIII-1 as colorless liquid.
Preparation of Compound IX-1
Dissolving compound VIII-1(13.00g) in 100mLEtOH, adding 6.0g palladium hydroxide carbon, hydrogenating at 20 deg.C under normal pressure for 16h, and detecting by TLC to complete the reaction. Filtering, concentrating the filtrate to prepare a sand column for chromatography and purification, and obtaining a compound IX-1 which is a colorless liquid 6.68g, wherein the yield of the two steps is as follows: 75.4 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C12H24O4Si：260；found：261。
Preparation of Compound X-1
Compound IX-1(6.30g, 0.0242mol, 1.0eq.) was dissolved in 80mL THF, PPh was added3(9.52g, 0.036mol, 1.5eq.), p-nitrobenzoic acid (6.06g, 0.036mol, 1.5eq.), DIAD (7.34g, 0.036mol, 1.5eq.) were added dropwise, the temperature was raised from 20 ℃ to 25 ℃, and after dropping, the reaction was carried out at 20 ℃ for 16 h. TLC detection reaction is complete, reaction liquid is concentrated, and the obtained product is purified by sand column chromatography, so that 5.8g of compound X-1 which is a white solid is obtained, and the yield is 58.5%.
Preparation of Compound XI-1
Compound X-1(5.80g, 0.0142mol, 1.0eq.) was dissolved in 80mL MeOH, K was added2CO3(0.5g, 0.00362mol, 0.25eq.), and the reaction was stirred at 20 ℃ for 16 h. TLC detection reaction is complete, methanol is removed by concentration at 35 ℃, and the obtained product is purified by sand column chromatography to obtain 2.60g of compound XI-1 as colorless liquid, and the yield is as follows: 70.3 percent.
Preparation of Compound I
Dissolving XI-1(2.60g, 0.010mol and 1.0eq.) in 50mL of MeOH, adding 10mL of 3N hydrochloric acid, reacting at 23 ℃ for 3h, concentrating the reaction solution, adding 20mL of MeOH, lithium hydroxide monohydrate (0.50g, 0.012mol and 1.2eq.), reacting at 30 ℃ for 30min, detecting by NMR that lactone is completely hydrolyzed, adding 10mL of 1.2N diluted hydrochloric acid for neutralization, and concentrating to obtain a light yellow solid. Dissolving with 20mL of water, decolorizing with 0.5g of activated carbon, filtering to obtain colorless liquid, concentrating, drying to obtain white solid, dissolving the solid with dimethyl tetrahydrofuran under heating, filtering to remove insoluble substances, and concentrating the mother liquor to obtain 1.75g of compound I as white solid with yield: 71.1 percent.1H-NMR:(400MHz，D2O)δ(ppm)4.45～4.38(m，1H)，2.37～2.36(d，4H)；(ESI-TOF)m/z：[M+H]+calcd for C5H8O4：246；found：247。
Example 2
Preparation of Compound III
Compound II (80.00g,0.454mol,1.0eq.) was dissolved in 600mL THF, Na was added2CO3(24.06g, 0.227mol, 0.5eq.) and TMSCN (45.04g, 0.454mol,1.0eq.), reacting at 20 ℃ for 3h, detecting by TLC that the reaction is complete, filtering, concentrating the filtrate to obtain 112.5g of compound III as red liquid, with yield: 90.0 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C15H21NO2Si：275；found：276。
Preparation of Compound IV-2
Dissolving the compound III (100.1g, 0.363mol, 1.0eq.) in 500mL EtOH, dropwise adding concentrated sulfuric acid (3.56g, 0.0363mol, 0.1eq.) under ice bath, controlling the temperature to be lower than 30 ℃, after dropwise adding, heating and refluxing at 55 ℃ for 4h, and generating a large amount of solid. And (5) detecting by TLC, and completing the reaction. Methanol was concentrated, 500mL of methyl tert-ether was added, filtration was carried out, the filtrate was washed with water, and after drying, concentration was carried out to obtain 78.3g of compound IV-2 as a brown liquid, yield: 87 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C14H18O4：250；found：251。
Preparation of Compound V
Compound IV (40.0g, 0.169mol, 1.0eq.) was dissolved in 150mL of peoh, 30mL of water was added, and potassium hydroxide (18.96g, 0.338mol, 2.0eq.) was added. The reaction was stirred at room temperature for 5 h. TLC detection of the reaction was complete, methanol was concentrated, 50mL of water was added, impurities were extracted with methyl tert-ether, pH was adjusted to 1 with 6N hydrochloric acid, extraction was performed with methyl tert-ether, the organic phases were combined, washed with saturated brine, dried, concentrated and washed with N-heptane to give compound V as a white solid 35.3 g.
Preparation of Compound VI
Compound V (35.3g) was recrystallized from DCM/PE-3/1180 mL to give compound VI as a white solid 25.3g in two steps: 67.3 percent.1H-NMR(400MHz，CDCl3)δ(ppm)：7.36～7.28(m，5H)，4.49(s，1H)，4.12～4.06(m，1H)，2.94～2.89(m，2H)，2.43～2.38(m，2H)。
Preparation of Compound VII-2
VI (8.00g, 0.036mol, 1.0eq.) was dissolved in 30mL EtOH, concentrated sulfuric acid (0.35g, 0.0036mol, 0.1eq.) was added dropwise, and the reaction was carried out at 20 ℃ for 2 h. And (3) detecting by LC-MS (liquid chromatography-mass spectrometry), completely reacting, concentrating the reaction solution, adding water and methyl tert-ether and sodium bicarbonate solid, stirring, separating, drying the organic phase, and concentrating to obtain 8.68g of a colorless liquid of the compound VII-2, wherein the yield is as follows: 96.3 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C14H18O4：250；found：251。
Preparation of Compound VIII-2
Compound VII-2(8.00g, 0.032mol, 1.0eq.) was dissolved in 60mL DCM, TEA (4.86g,0.048mol, 1.5eq.) was added, and TBSCl (7.23g, 0.048mol, 1.5eq.) was added dropwise in an ice bath, the temperature was controlled below 20 ℃ and the reaction was carried out for 16h at 20 ℃. TLC detection has a small amount of raw material residue, the reaction solution is added with 20mL of water and washed once, then washed once with 10mL of saturated salt, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated to obtain 10.3g of compound VIII-2 as colorless liquid.
Preparation of Compound IX-2
Compound VIII-2(10.3g) was dissolved in 100mL EtOH, 5.0g palladium on carbon was added, and the reaction was hydrogenated at 50 ℃ under normal pressure for 20 hours, and the reaction was completed as detected by TLC. Filtering, concentrating the filtrate to prepare a sand column for chromatography and purification, and obtaining a compound IX-2 which is 6.31g of colorless liquid, wherein the yield is as follows: 71.8 percent.
Preparation of Compound X-2
Compound IX-2(6.31g, 0.023mol, 1.0eq.) was dissolved in 60mL THF, PPh was added3(5.45g, 0.0208mol, 0.9eq.), p-nitrobenzoic acid (3.84g, 0.023mol, 1.0eq.), DEAD (3.62g, 0.208mol, 0.9eq.) added dropwise at a temperature of from 10 ℃ to 25 ℃ and reacted for 8h at 40 ℃. TLC detection reaction is complete, reaction liquid is concentrated, and the obtained product is purified by sand column chromatography, so that 5.6g of compound X-2 which is a white solid is obtained, and the yield is 57.4%.
Preparation of Compound XI-2
Compound X-2(5.17g, 0.0122mol, 1.0eq.) was dissolved in 80mL of methanol, cesium carbonate (1.99g, 0.0061mol, 0.5eq.) was added, and the reaction was stirred at 20 ℃ for 16 h. TLC detection reaction is complete, methanol is removed by concentration at 35 ℃, and the obtained product is purified by sand column chromatography to obtain 2.80g of compound XI-2 as colorless liquid, and the yield is as follows: 83.6 percent.
Preparation of Compound I
Dissolving XI-2(2.74g, 0.010mol and 1.0eq.) in 50mL of methanol, adding 10mL of 6N hydrochloric acid, reacting at 23 ℃ for 3h, concentrating the methanol, adding 20mL of ethanol, barium hydroxide (1.714g, 0.010mol and 1.0eq.), reacting at 30 ℃ for 30min, detecting the lactone by NMR, adding 1.0N diluted hydrochloric acid for neutralization, and concentrating to obtain a light yellow solid. Dissolving with 20mL of water, decolorizing with 0.5g of activated carbon, filtering to obtain colorless liquid, concentrating, drying to obtain white solid, dissolving the solid with dimethyl tetrahydrofuran under heating, filtering to remove insoluble substances, and concentrating the mother liquor to obtain 1.80g of compound I as white solid with yield: 73.0 percent.1H-NMR:(400MHz，D2O)δ(ppm)4.45～4.38(m，1H)，2.37～2.36(d，4H)；(ESI-TOF)m/z：[M+H]+calcd for C5H8O4：246；found：247。
Example 3
Preparation of Compound III
Dissolving a compound II (80.00g,0.454mol,1.0eq.) in 1000mL acetonitrile, adding cesium carbonate (295.8g, 0.908mol, 2.0eq.) and TMSCN (90.07g,0.908mol, 2.0eq.), reacting at 20 ℃ for 3h, detecting by TLC that the reaction is complete, filtering, and concentrating the filtrate to obtain a compound III as a red liquid 112.5g, yield: 90.0 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C15H21NO2Si：275；found：276。
Preparation of Compound IV-1
Compound III (102.1g, 0.370mol, 1.0eq.) was dissolved in 500mL of methanol and SOCl was added dropwise under ice-bath2(132.32g, 1.11mol, 3.0eq.), controlling the temperature to be lower than 35 ℃, after finishing dripping, heating and refluxing at 55 ℃ for reaction for 5 hours, and generating a large amount of solid. And (5) detecting by TLC, and completing the reaction. Methanol was concentrated, 500mL of methyl tert-ether was added, filtration was carried out, the filtrate was washed with water, and after drying, concentration was carried out to obtain 80.07g of compound IV-1 as a brown liquid, yield: 91.6 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C13H16O4：236；found：237。
Preparation of Compound V
Compound IV-1(40.0g, 0.169mol, 1.0eq.) was dissolved in 150mL of methanol, 30mL of water was added, and lithium hydroxide monohydrate (10.63g, 0.253mol, 1.5eq.) was added. The reaction is carried out for 4h at 20 ℃. TLC after completion of the reaction, methanol was concentrated, 50mL of water was added, impurities were extracted with methyl tert-ether, pH was adjusted to 1 with 6N hydrochloric acid, extracted with methyl tert-ether, the organic phases were combined, washed with saturated brine, dried, concentrated and washed with N-heptane to give compound V as a white solid, 35.1 g.
Preparation of Compound VI
Compound V (35.1g) was recrystallized from EA/n-hexane 3/1220 mL to give compound VI as a white solid 23.0g, two-step yield: 61.2 percent. 1H-NMR (400MHz, CDCl)3)δ(ppm)：7.36～7.28(m，5H)，4.49(s，1H)，4.12～4.06(m，1H)，2.94～2.89(m，2H)，2.43～2.38(m，2H)。
Preparation of Compound VII-1
VI (8.00g, 0.036mol, 1.0eq.) was dissolved in 30mL of methanol and added dropwiseAdding SOCl2(12.85g, 0.108mol, 3.0eq.) is strongly discharged and released heat, after dropping, the reaction is carried out for 2h at 20 ℃, LC-MS detection shows that the reaction is complete, water and methyl tert-ether and sodium bicarbonate solid are added, after stirring, liquid separation and organic phase drying, the mixture is concentrated to obtain 8.20g of colorless liquid of the compound VII-1, and the yield is 96.4%.
Preparation of Compound VIII-1
Compound VII-1(8.00g, 0.034mol,1.0eq.) was dissolved in 60mL DCM, DIPEA (4.39g, 0.034mol,1.0eq.) was added, and TBSCl (6.12g, 0.034mol,1.0eq.) was added dropwise in an ice bath, the temperature was controlled below 20 ℃, and the reaction was carried out for 16h at 20 ℃. TLC detection has a small amount of raw material residue, the reaction solution is added with 20mL of water and washed once, then washed once with 10mL of saturated salt solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated to obtain 12.0g of compound VIII-1 as colorless liquid.
Preparation of Compound IX-1
Dissolving compound VIII-1(12.00g) in 100mL ethanol, adding 6.0g palladium hydroxide carbon, carrying out hydrogenation reaction at 45 ℃ under normal pressure for 16h, and detecting the reaction completion by TLC. Filtering, concentrating the filtrate to prepare a sand column for chromatography and purification, and obtaining a compound IX-1 which is 7.01g of colorless liquid, wherein the yield is as follows: 79.1 percent.
Preparation of Compound X-1
Compound IX-1(7.01g, 0.0269mol, 1.0eq.) was dissolved in 60mL THF, PPh was added3(14.1g,0.0538mol, 2.0eq.), p-nitrobenzoic acid (6.73g, 0.040mol, 1.5eq.), DIAD (10.87g, 0.0538mol, 2.0eq.) was added dropwise, the temperature was raised from 20 ℃ to 25 ℃ and the reaction was carried out for 16h at 20 ℃. TLC detection reaction is complete, reaction liquid is concentrated, and the obtained product is purified by sand column chromatography, so that 6.3g of the compound X-1 which is a white solid is obtained, and the yield is 57.1%.
Preparation of Compound XI-1
Compound X-1(5.00g, 0.0122mol, 1.0eq.) was dissolved in 80mL of methanol, sodium carbonate (1.29g, 0.0122mol, 1.0eq.) was added, and the reaction was stirred at 20 ℃ for 16 h. TLC detection reaction is complete, methanol is removed by concentration at 35 ℃, and the obtained product is purified by sand column chromatography to obtain a compound XI-1 which is 2.68g of colorless liquid, and the yield is as follows: 84.3 percent.
Preparation of Compound I
Mixing XI-1(2.60g, 0)010mol, 1.0eq.) is dissolved in 50mL of methanol, 10mL of 6N hydrochloric acid is added, reaction is carried out at 23 ℃ for 3h, methanol is concentrated, 20mL of ethanol, sodium hydroxide (1.714g, 0.010mol, 1.5eq.) are added, reaction is carried out at 30 ℃ for 30min, 1.0N of dilute hydrochloric acid is added for neutralization, and light yellow solid is obtained by concentration. Dissolving with 20mL of water, decolorizing with 0.5g of activated carbon, filtering to obtain colorless liquid, concentrating, drying to obtain white solid, dissolving the solid with dimethyl tetrahydrofuran under heating, filtering to remove insoluble substances, and concentrating the mother liquor to obtain 1.92g of compound I as white solid with yield: 78.0 percent.1H-NMR:(400MHz，D2O)δ(ppm)4.45～4.38(m，1H)，2.37～2.36(d，4H)；(ESI-TOF)m/z：[M+H]+calcd for C5H8O4：246；found：247。
Example 4
Preparation of Compound III
Dissolving a compound II (80.00g,0.454mol,1.0eq.) in 600mL of DMF, adding TMSCN (54.05g,0.545mol,1.2eq.) to react at 20 ℃ for 3h, detecting by TLC that the reaction is complete, pouring the reaction liquid into water, EA extracting, combining organic phases, drying, and concentrating to obtain a compound III as a red liquid 120.0g, with the yield: 96.0 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C15H21NO2Si：275；found：276。
Preparation of Compound IV-1
Dissolving the compound III (100.1g, 0.363mol, 1.0eq.) in 500mL of methanol, dropwise adding concentrated sulfuric acid (17.82g, 0.181mol, 0.5eq.) in an ice bath, controlling the temperature to be lower than 30 ℃, heating and refluxing at 55 ℃ for 3 hours after dropwise adding, and generating a large amount of solid. And (5) detecting by TLC, and completing the reaction. Methanol was concentrated, 500mL of methyl tert-ether was added, filtration was carried out, the filtrate was washed with water, and after drying, concentration was carried out to obtain compound IV-1 as a brown liquid 79.41g, yield: 92.6 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C13H16O4：236；found：237。
Preparation of Compound V
Will combine withSubstance IV (40.0g, 0.169mol, 1.0eq.) was dissolved in 150mL of methanol, 30mL of water was added, and Ba (OH) was further added2(87.03g, 0.507mol, 3.0 eq.). The reaction is carried out for 4h at 20 ℃. TLC detected the reaction was complete, methanol was concentrated, 50mL of water was added, impurities were extracted with methyl tert-ether, pH was adjusted to 1 with 6N hydrochloric acid, extracted with methyl tert-ether, the organic phases were combined, washed with saturated brine, dried, concentrated and washed with N-heptane to give compound V as a white solid, 28.1 g.
Preparation of Compound VI
Compound V (28.1g) was recrystallized from EA/PE 3.5/1200 mL to give compound VI as a white solid 17.0g, two-step yield: 45.3 percent.1H-NMR(400MHz，CDCl3)δ(ppm)：7.36～7.28(m，5H)，4.49(s，1H)，4.12～4.06(m，1H)，2.94～2.89(m，2H)，2.43～2.38(m，2H)。
Preparation of Compound VII
VI (8.00g, 0.036mol, 1.0eq.) is dissolved in 30mL of methanol, concentrated sulfuric acid (1.76g, 0.018mol, 0.5eq.) is added dropwise, the gas is discharged violently to release heat, and the reaction is carried out for 2h at 20 ℃ after the dripping is finished. And (3) detecting by LC-MS (liquid chromatography-mass spectrometry), completely reacting, concentrating the reaction solution, adding water and methyl tert-ether and sodium bicarbonate solid, stirring, separating, drying the organic phase, and concentrating to obtain 7.51g of a colorless liquid of the compound VII-1, wherein the yield is as follows: 88.3 percent.
Preparation of Compound VIII-1
Dissolving compound VII (8.00g,0.034mol,1.0eq.) in 60mL DCM, adding imidazole (4.63g, 0.068mol, 2.0eq.), and adding TBSCl (10.2g,0.068mol, 2.0eq.) dropwise under ice bath, controlling the temperature to be lower than 20 ℃, and reacting for 16h at 20 ℃. TLC detection raw material reaction is finished, 20mL water is added into reaction liquid for washing once, 10mL saturated salt water is added for washing once, anhydrous magnesium sulfate is dried, filtration is carried out, and the filtrate is concentrated to obtain 12.3g of compound VIII-1 as colorless liquid.
Preparation of Compound IX-1
Compound VIII-1(12.3g) was dissolved in 100mL of methanol, followed by addition of 5.0g of palladium on carbon hydroxide, hydrogenation reaction at 50 ℃ under normal pressure for 20 hours, and completion of the reaction was detected by TLC. Filtering, concentrating the filtrate to prepare a sand column for chromatography and purification, and obtaining a compound IX-1 which is a colorless liquid 6.93g, with the yield: 78.3 percent.
Preparation of Compound X
Compound IX (7.01g, 0.0269mol, 1.0eq.) was dissolved in 60mL THF, PPh was added3(8.46g, 0.0322mol, 1.2eq.), p-nitrobenzoic acid (8.99g, 0.0538mol, 2.0eq.), DIAD (6.53g, 0.0323mol, 1.2eq.) was added dropwise, the temperature was raised from 20 ℃ to 25 ℃ and the reaction was completed at 60 ℃ for 6 h. TLC detection reaction is complete, reaction liquid is concentrated, and the obtained product is purified by sand column chromatography, so that 5.3g of a white solid of the compound X is obtained, and the yield is 48.1%.
Preparation of Compound XI
Compound X (5.00g, 0.0122mol, 1.0eq.) was dissolved in 50mL of methanol, sodium methoxide (0.066g, 0.00122mol, 0.1eq.) was added, and the reaction was stirred at 20 ℃ for 16 h. TLC detection reaction is complete, methanol is removed by concentration at 35 ℃, and the obtained product is purified by sand column chromatography to obtain 2.48g of compound XI as colorless liquid, and the yield is as follows: 78.1 percent.
Preparation of Compound I
Dissolving XI (2.00g, 0.0077mol, 1.0eq.) in 20mL of methanol, adding 6mL of 3N hydrochloric acid, reacting at 20 ℃ for 3h, concentrating the methanol, adding 20mL of ethanol, potassium hydroxide (0.86g, 0.0154mol, 2.0eq.), reacting at 30 ℃ for 30min, adding 1.0N diluted hydrochloric acid, neutralizing, and concentrating to obtain a light yellow solid. Dissolving with 20mL of water, decolorizing with 0.5g of activated carbon, filtering to obtain colorless liquid, concentrating, drying to obtain white solid, dissolving the solid with dimethyl tetrahydrofuran under heating, filtering to remove insoluble substances, and concentrating the mother liquor to obtain 1.72g of compound I as white solid with yield: 90.7 percent.1H-NMR:(400MHz，D2O)δ(ppm)4.45～4.38(m，1H)，2.37～2.36(d，4H)；(ESI-TOF)m/z：[M+H]+calcd for C5H8O4：246；found：247。
Claims (11)
1. A method of preparing a synthetic compound VI comprising:
wherein: r1Is methyl or ethyl; in the step of preparing compound V from compound IV, the reaction is completedAcidifying with acid; compound V is prepared into compound VI through recrystallization in dichloromethane/n-heptane, dichloromethane/petroleum ether, ethyl acetate/n-heptane or ethyl acetate/petroleum ether.
2. The method of claim 1, wherein: in the step of preparing the compound III from the compound II, the molar ratio of the compound II to the trimethylsilyl cyanide is 1: 1-1: 2.
3. The method of claim 1, wherein: in the step of preparing the compound III from the compound II, a base 1 can be added in the reaction; the base 1 is selected from potassium carbonate, sodium carbonate or cesium carbonate; the molar ratio of the compound II, the trimethylsilyl cyanide and the alkali 1 is 1: 1-2: 0.5-2.
4. The method of claim 1, wherein: in the step of preparing the compound IV from the compound III, the acid 1 is thionyl chloride or concentrated sulfuric acid; the alcohol 1 is methanol or ethanol; the molar ratio of the compound III to the acid 1 is 1: 0.1-1: 3.
5. The method of claim 1, wherein: in the step of preparing compound V from compound IV, the base 2 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide.
6. A process for the preparation of compound I, characterized in that compound VI, prepared according to claim 1, is prepared by the following reaction:
wherein: r1Is methyl or ethyl.
7. The method of claim 6, wherein: in the step of preparing the compound VII from the compound VI, the acid 2 is thionyl chloride or concentrated sulfuric acid; the alcohol 2 is methanol or ethanol; the molar ratio of the compound VI to the acid 2 is 1: 0.1-1: 2.
8. The method of claim 6, wherein: in the step of preparing the compound VIII from the compound VII, the base 3 is selected from imidazole, triethylamine or N, N-diisopropylethylamine; the molar ratio of the compound VII, the tert-butyldimethylsilyl chloride and the alkali 3 is 1: 1.0-2.0; the reaction temperature range is 0-40 ℃.
9. The method according to claim 6, wherein: in the step of preparing the compound X from the compound IX, the azo reagent is diisopropyl azodicarboxylate or diethyl azodicarboxylate; compounds IX, PPh3And the azo reagent in a molar ratio range of: 1: 0.9-2; the reaction temperature range is 10-60 ℃.
10. The method of claim 6, wherein: compound X in the step of preparing compound XI, the base 4 is selected from potassium carbonate, cesium carbonate, sodium methoxide or sodium ethoxide; the molar ratio of the compound X to the alkali 4 is 1: 0.1-1: 1.
11. The method of claim 6, wherein: in the step of preparing the compound I by using the compound XI, the base 5 is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide; the molar ratio of the compound XI to the alkali 5 is 1: 1-1: 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811007287.5A CN109096098B (en) | 2018-08-31 | 2018-08-31 | Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811007287.5A CN109096098B (en) | 2018-08-31 | 2018-08-31 | Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109096098A CN109096098A (en) | 2018-12-28 |
| CN109096098B true CN109096098B (en) | 2021-04-23 |
Family
ID=64864343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811007287.5A Active CN109096098B (en) | 2018-08-31 | 2018-08-31 | Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109096098B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112279759B (en) * | 2019-07-25 | 2023-10-03 | 南京富润凯德生物医药有限公司 | Method for synthesizing 2-fluorocyclobutyl methylamine and intermediate thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040978A (en) * | 1988-09-09 | 1990-04-04 | 日本化药株式会社 | New New cyclobutane derivative and preparation method thereof |
| US8062651B1 (en) * | 2004-03-16 | 2011-11-22 | The United States Of America As Represented By The Secretary Of Agriculture | Attractant pheromone for the male pink hibiscus mealybug, Maconellicoccus hirsutus (Green) (Homoptera: Pseudococcidae) |
| WO2016040223A1 (en) * | 2014-09-09 | 2016-03-17 | Bristol-Myers Squibb Company | Cyclobutane containing carboxylic acid gpr120 modulators |
| CN107903161A (en) * | 2017-11-23 | 2018-04-13 | 上海毕路得医药科技有限公司 | A kind of synthetic method of cis 3 hydroxycyclobutyl formic acid |
| CN108129288A (en) * | 2017-12-27 | 2018-06-08 | 上海毕得医药科技有限公司 | A kind of synthetic method of trans- -3- hydroxycyclobutyls formic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2767478A1 (en) * | 2009-07-11 | 2011-01-20 | Bayer Pharma Aktiengesellschaft | Radiolabelling method using cycloalkyl groups |
| CA2968836A1 (en) * | 2016-06-13 | 2017-12-13 | Gilead Sciences, Inc. | Fxr (nr1h4) modulating compounds |
-
2018
- 2018-08-31 CN CN201811007287.5A patent/CN109096098B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040978A (en) * | 1988-09-09 | 1990-04-04 | 日本化药株式会社 | New New cyclobutane derivative and preparation method thereof |
| US8062651B1 (en) * | 2004-03-16 | 2011-11-22 | The United States Of America As Represented By The Secretary Of Agriculture | Attractant pheromone for the male pink hibiscus mealybug, Maconellicoccus hirsutus (Green) (Homoptera: Pseudococcidae) |
| WO2016040223A1 (en) * | 2014-09-09 | 2016-03-17 | Bristol-Myers Squibb Company | Cyclobutane containing carboxylic acid gpr120 modulators |
| CN107903161A (en) * | 2017-11-23 | 2018-04-13 | 上海毕路得医药科技有限公司 | A kind of synthetic method of cis 3 hydroxycyclobutyl formic acid |
| CN108129288A (en) * | 2017-12-27 | 2018-06-08 | 上海毕得医药科技有限公司 | A kind of synthetic method of trans- -3- hydroxycyclobutyls formic acid |
Non-Patent Citations (3)
| Title |
|---|
| "3-羟基氧杂环丁烷的合成及其对甲苯磺酸酯与碘化钠的交换";王学勤等;《化学学报》;19841231;第1168-1172页 * |
| "Applications of C-H Functionalization Logic to Cyclobutane Synthesis";W. R. Gutekunst et al.;《J. Org. Chem.》;20140218;第79卷;第2430-2452页 * |
| "Improved synthesis of anti-[18F]FACBC: improved preparation of labeling precursor and automated radiosynthesis";J. Mc Conathy et al.;《Applied Radiation and Isotopes》;20031231;第58卷;第657-666页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109096098A (en) | 2018-12-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100355732C (en) | Preparation of 2-Cl-5-F-nicotinate and nicotonic acid | |
| JP2021530505A (en) | Chemical process to prepare phenylpiperidinyl indole derivatives | |
| US9187419B2 (en) | Intermediates of sitagliptin and preparation process thereof | |
| EP2590943B1 (en) | Process and intermediates for preparation of an active ingredient | |
| CN102317256B (en) | Preparation method for racecadotril | |
| CN109096098B (en) | Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid | |
| EP2247572B1 (en) | A one-pot process for preparing 3-(2,2,2-trimethylhydrazinium)propionate dihydrate | |
| CN110981779B (en) | Synthesis method of R-2- (2, 5-difluorophenyl) pyrrolidine | |
| US20150299105A1 (en) | New process | |
| CN104744390A (en) | Preparation method of ezetimibe internmediate ketone | |
| CN107674016B (en) | Preparation method of telaprevir intermediate and intermediate thereof | |
| CN111116533B (en) | Zanamivir and ranamivir intermediate and synthesis method thereof | |
| CN112479967B (en) | Biliverdin compound, and preparation method and application thereof | |
| CN107365301B (en) | Synthesis method of crizotinib and preparation method of intermediate thereof | |
| CN109575021B (en) | Preparation method of thuja occidentalis | |
| CN112174798B (en) | Synthesis method of Sakuba/valsartan sodium LCZ696 | |
| CN114621068A (en) | Preparation method of 3-hydroxy-1-adamantane methyl ketone and method for synthesizing saxagliptin | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN113045416A (en) | Preparation method of (R) -3-hydroxybutyryl- (R) -3-hydroxybutyl ester | |
| CN109988070B (en) | Intermediate of trans-1-hydroxy-1- (trifluoromethyl) -3-aminocyclobutane hydrochloride, preparation method and application | |
| CN101654426B (en) | Method for preparing ilomastat | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| CN116903468B (en) | Preparation method of milbelin intermediate | |
| CN103193600B (en) | The preparation method of rivastigmine intermediate | |
| CN111039901B (en) | Process for producing 1, 3-dicarbonyl compound and intermediate thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |