CN119462358A - A process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid - Google Patents
A process for synthesizing trans-3-hydroxycyclobutanecarboxylic acid Download PDFInfo
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- CN119462358A CN119462358A CN202411595448.2A CN202411595448A CN119462358A CN 119462358 A CN119462358 A CN 119462358A CN 202411595448 A CN202411595448 A CN 202411595448A CN 119462358 A CN119462358 A CN 119462358A
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- trans
- hydroxycyclobutane
- hydroxycyclobutanecarboxylic acid
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- methylbenzylamine
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- ZSHGVMYLGGANKU-UHFFFAOYSA-N 3-hydroxycyclobutane-1-carboxylic acid Chemical compound OC1CC(C(O)=O)C1 ZSHGVMYLGGANKU-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 32
- 230000008569 process Effects 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- -1 3-oxo-cyclobutane formic acid ester Chemical class 0.000 claims abstract description 19
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims abstract description 9
- OBAJXDYVZBHCGT-UHFFFAOYSA-N tris(pentafluorophenyl)borane Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1B(C=1C(=C(F)C(F)=C(F)C=1F)F)C1=C(F)C(F)=C(F)C(F)=C1F OBAJXDYVZBHCGT-UHFFFAOYSA-N 0.000 claims abstract description 9
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical class CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000009467 reduction Effects 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 6
- IENOFRJPUPTEMI-UHFFFAOYSA-N 3-oxocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CC(=O)C1 IENOFRJPUPTEMI-UHFFFAOYSA-N 0.000 claims description 5
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 5
- IHLHSAIBOSSHQV-UHFFFAOYSA-N methyl 3-oxocyclobutane-1-carboxylate Chemical compound COC(=O)C1CC(=O)C1 IHLHSAIBOSSHQV-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- ZSHGVMYLGGANKU-JPYJGEKTSA-N O[C@H]1C[C@H](C(O)=O)C1 Chemical class O[C@H]1C[C@H](C(O)=O)C1 ZSHGVMYLGGANKU-JPYJGEKTSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- BYKHAEUVLSBWSU-UHFFFAOYSA-N methyl 3-hydroxycyclobutane-1-carboxylate Chemical compound COC(=O)C1CC(O)C1 BYKHAEUVLSBWSU-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GAZCHQWBPAPJBR-UHFFFAOYSA-N C(=O)OC.OC1CCC1 Chemical compound C(=O)OC.OC1CCC1 GAZCHQWBPAPJBR-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical class N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- BXBRFSMPBOTZHJ-UHFFFAOYSA-N ethyl 3-oxocyclobutane-1-carboxylate Chemical compound CCOC(=O)C1CC(=O)C1 BXBRFSMPBOTZHJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
-
- 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
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- 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
- C07B2200/09—Geometrical 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a process method for synthesizing trans-3-hydroxycyclobutane carboxylic acid, which takes 3-oxo-cyclobutane formic acid ester as a raw material, adopts aluminum triisopropoxide to reduce carbonyl under the catalysis of tris (pentafluorophenyl) borane to generate trans-as a main cis-trans isomer, then hydrolyzes in alkali to obtain a 3-hydroxycyclobutane carboxylic acid cis-trans mixture, then salifies with alpha-methylbenzylamine compounds for purification to obtain trans-3-hydroxycyclobutane carboxylic acid amine salt, and then dissociates to obtain trans-3-hydroxycyclobutane carboxylic acid. The method improves the selectivity of the trans-product during carbonyl reduction, separates cis-trans isomers by salifying, purifies single trans-3-hydroxycyclobutane carboxylic acid, has mild process conditions, is simple and convenient to operate, and is suitable for technological production.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a process method for synthesizing trans-3-hydroxycyclobutane carboxylic acid.
Background
Trans-3-hydroxycyclobutane carboxylic acid, english name trans-3-Hydroxycyclobutanecar boxylic acid, CAS 1268521-85-2, because of its unique stereochemical structural properties, is applied to various fine chemicals, pharmaceutical synthesis and biomedical fields, such as butorphanol metabolite and NTRK kinase inhibitor, and relates to the application of the compound. The market demand of the product is increased, and the product has good prospect.
At present, the compound has more and more application values, however, few synthesis methods of trans-3-hydroxy-cyclobutanecarboxylic acid are reported in literature, and few synthesis methods of intermediate trans-3-hydroxy-cyclobutanecarboxylic acid ester are also disclosed, and mainly comprise the following two methods:
first, the trans-product is obtained by utilizing the polarity difference of cis-trans isomers. Literature European Journal ofOrganic Chemistry,2024,27, e202400493 (1 of 9) reports that 3-oxocyclobutanecarboxylic acid esters give cis-predominantly cis-trans isomer mixtures under sodium borohydride reduction, cis/trans being 4/1. Patent US2009/118287 discloses that 3-hydroxycyclobutane methyl formate is used as a raw material, reacts with bromobenzyl under the action of NaH, and the corresponding trans-product is obtained through column chromatography separation, wherein the yield is only 15.4%. The existing method for separating cis-trans isomers has low yield of trans-products, difficult purification and difficult mass production.
Second, the cis isomer is converted to the trans isomer by configuration inversion. Patent WO2015/66413 takes cis-3-hydroxycyclobutane methyl formate as a raw material, after the cis-3-hydroxycyclobutane methyl formate reacts with methanesulfonyl chloride, the cis-3-hydroxycyclobutane methyl formate reacts with potassium acetate for 21 hours at 120 ℃ to generate configuration inversion, and acetyl is removed under the action of sodium methoxide to obtain trans-3-hydroxycyclobutane methyl formate.
Patent CN108129288 uses 3-oxo-cyclobutanecarboxylic acid ester as raw material, and uses reducing agent to make reduction so as to obtain single cis-3-hydroxy-cyclobutanecarboxylic acid ester, then uses Mitsunobu reaction and hydrolysis three-step reaction to obtain trans-3-hydroxy-cyclobutanecarboxylic acid, and the reducing agent (triethyllithium borohydride, tri-tert-butoxylithium aluminum hydride or tri-sec-butyllithium borohydride) is used in the invented method, and is expensive and inflammable, and its raw material cost is high, and when the Mitsunobu reaction is implemented, a large quantity of waste solids containing triphenylphosphine oxide are produced, so that it is not favourable for environmental protection, and is unsuitable for industrial production.
Therefore, it is necessary to develop a suitable process to solve the problems of efficiently producing more trans-products or how to separate cis-trans isomers, so as to facilitate industrial production.
Disclosure of Invention
In order to overcome the problems, the invention discloses a process method for synthesizing trans-3-hydroxycyclobutane carboxylic acid. The method takes 3-oxo-cyclobutaneformate as a raw material, adopts triisopropanol aluminum to reduce carbonyl under the catalysis of tris (pentafluorophenyl) borane to generate trans-form as a main cis-trans isomer, then hydrolyzes in alkali to obtain a 3-hydroxy-cyclobutaneformate cis-trans mixture, then salifies with alpha-methylbenzylamine compounds for purification to obtain trans-3-hydroxy-cyclobutaneformate salt, and then dissociates to obtain trans-3-hydroxy-cyclobutaneformate. The method improves the selectivity of the trans-product during carbonyl reduction, separates cis-trans isomers by salifying, purifies single trans-3-hydroxycyclobutane carboxylic acid, has mild process conditions, is simple and convenient to operate, and is suitable for technological production.
The invention provides a process method for synthesizing trans-3-hydroxy cyclobutanecarboxylic acid, which adopts the following equation:
the method comprises the following steps:
firstly, carrying out carbonyl reduction on 3-oxo-cyclobutanecarboxylic acid ester and aluminum triisopropoxide under the catalysis of tris (pentafluorophenyl) borane to obtain trans-based 3-hydroxy-cyclobutanecarboxylic acid ester (compound 1);
Step two, carrying out hydrolysis reaction on trans-dominant 3-hydroxy cyclobutanecarboxylic acid ester (compound 1) and alkaline aqueous solution to obtain trans-dominant 3-hydroxy cyclobutanecarboxylic acid (compound 2);
Thirdly, salifying trans-main 3-hydroxy-cyclobutanecarboxylic acid (compound 2) and alpha-methylbenzylamine compounds in an organic solvent, filtering to obtain trans-3-hydroxy-cyclobutanecarboxylic acid amine salt (compound 3), adding dilute hydrochloric acid into water to adjust the pH value to be acidic, and treating to obtain trans-3-hydroxy-cyclobutanecarboxylic acid.
Further, in the first step, the molar ratio of 3-oxo-cyclobutanecarboxylic acid ester, aluminum triisopropoxide and tris (pentafluorophenyl) borane is 1.0:0.4-0.5:0.03-0.05.
Further, in the first step, the reaction temperature is 0-25 ℃, and the reaction solvent is selected from isopropanol.
Further, in the second step, the alkaline aqueous solution is selected from KOH or NaOH aqueous solution, and the reaction temperature is 20-30 ℃.
Further, in the third step, the α -methylbenzylamine compound is selected from D- α -methylbenzylamine, L- α -methylbenzylamine, or DL- α -methylbenzylamine, preferably L- α -methylbenzylamine.
Further, in the third step, the mol ratio of the trans-form to the main 3-hydroxycyclobutane carboxylic acid (compound 2) to the alpha-methylbenzylamine compound is 1.0:1.0.
Further, in the third step, the organic solvent is selected from acetone, and the reaction temperature is 20-80 ℃.
Further, in the third step, ph=1-2 is adjusted by dilute hydrochloric acid, and the trans-3-hydroxycyclobutane carboxylic acid (compound 4) is obtained by extraction with dichloromethane, concentration and beating with n-heptane.
The invention has the following advantages:
1. the 3-oxo-cyclobutaneformate is used as a raw material, under the action of aluminum isopropoxide and tris (pentafluorophenyl) borane, the trans selectivity is improved, the trans-based reduction product is obtained, and the yield of preparing the trans-3-hydroxy-cyclobutaneformate is greatly improved.
2. The single trans-salt is obtained by utilizing a salt formation purification method of the cis-trans mixture and the alpha-methylbenzylamine compound, and then the trans-3-hydroxycyclobutane carboxylic acid is obtained by dissociation, so that the GC purity is more than 98%, and the problem that the cis-trans isomer is difficult to separate and purify is solved without column chromatography.
3. The method has the advantages of cheap and easily obtained raw materials, simple and convenient operation, high yield, safety and environmental protection, and suitability for technological production.
Drawings
FIG. 1 is a 1 HNMR spectrum of the trans-3-hydroxycyclobutane carboxylic acid product of example 4;
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Aluminum triisopropoxide (40.8 g,0.2 mol), tris (pentafluorophenyl) borane (10.2 g,0.02 mol) and 150mL isopropyl alcohol were added to the reaction flask under nitrogen, methyl 3-oxocyclobutanoate (51.2 g,0.4 mol)/100 mL isopropyl alcohol solution was added dropwise at 0-5 ℃, after stirring for 16 hours at room temperature, methyl 3-oxocyclobutanoate <1% as the starting material in GC, methyl 3-hydroxycyclobutanoate as the cis-trans isomer of compound 1 was 96.9% (trans/cis=74.4/25.6), 80mL 30% naoh solution was added dropwise at 20-30 ℃, after stirring for 5 hours at a temperature of 20-30 ℃, the compound 1<1% as the intermediate in GC was concentrated under reduced pressure, 200mL methylene chloride was added, 10% hydrochloric acid was added dropwise at 0-10 ℃ to adjust pH 4-5, layering was performed, the aqueous layer was extracted 2 times, 200mL of methylene chloride was combined, saturated salt was washed with water each time, 100% heptane was added under reduced pressure, and after concentrating the organic layer was dried under reduced pressure, and 2.97% dry (cis-2.8% dry, 2.8% as the cis-2.8% as the solid was obtained by drying (cis-2.8%).
Example 2
Aluminum triisopropoxide (32.7 g,0.16 mol), tris (pentafluorophenyl) borane (6.2 g,0.012 mol) and 150mL of isopropyl alcohol were added to the reaction flask under nitrogen protection, ethyl 3-oxocyclobutanoate (56.8 g,0.4 mol)/100 mL of isopropyl alcohol solution was added dropwise at 0-5 ℃, after stirring at room temperature for 16 hours, methyl 3-oxocyclobutanoate as a starting material was <1% in GC, methyl 3-hydroxycyclobutane formate as a cis-trans isomer of compound 1 was 96.4% (trans/cis=73.7/26.3), 80mL of 30% naoh solution was added dropwise at 20-30 ℃, after stirring at 5 hours under heat preservation, the compound 1<1% in GC was concentrated under reduced pressure, 200mL of methylene chloride was added dropwise at 0-10 ℃ to adjust ph=4-5, layering was performed, the aqueous layer was extracted 2 times, 200mL of methylene chloride was combined, saturated brine was washed, the organic layer was concentrated under reduced pressure, 100mL of normal saline was dried, and 1:6.88% of cis-heptane was obtained as a solid (cis-6.7.26.3%) was dried, and 1:6.88% of cis-heptane was obtained as a solid.
Example 3
Compound 2 (GC 97.3% (trans/cis=74.2/25.8) (41.8 g,0.36 mol) and 400mL of acetone were added to the reaction flask, stirred to complete dissolution, L- α -methylbenzylamine (43.6 g,0.36 mol)/230 mL of acetone solution was added dropwise, a white solid was gradually precipitated, heated to 70-80 ℃ and stirred for 1 hour, the solid was complete dissolution, the system was clarified, slowly cooled to room temperature to precipitate a white solid, filtered to obtain a white solid compound 3 trans-3-hydroxycyclobutane carboxylic acid L- α -methylbenzylamine salt 47.2g, 1 HNMR purity: 98.9% (trans/cis=72/1), yield 55.3%.
The compound 2 (1 eq) and the alpha-methylbenzylamine (1 eq) obtained by the method of example 1 are used for salifying in different solvents, and the experimental results are as follows:
Example 4
70ML of water and compound 3 (47.2 g,0.20mol, trans/cis=72/1) were added to the reaction flask, stirred, 10-20 ℃ was added dropwise with 45mL of 20% HCl solution pH=1-2, dichloromethane was extracted (100 mL×3), the organic layers were combined, saturated brine was washed, the organic layers were concentrated under reduced pressure and then slurried with 40mL of n-heptane for 1 hour, and filtered to give 20.3g of trans-3-hydroxycyclobutane carboxylic acid as a white solid, GC:98.8%, yield 87.3%, and 1 H-NMR characterization as shown in FIG. 1.
Comparative example 1
Aluminum triisopropoxide (40.8 g,0.2 mol) and 150mL of isopropanol are added into a reaction bottle under the protection of nitrogen, 3-oxocyclobutanecarboxylic acid methyl ester (51.2 g,0.4 mol)/100 mL of isopropanol solution is dropwise added at 0-5 ℃, after the dropwise addition, stirring is carried out at room temperature for 16 hours, 3-oxocyclobutanecarboxylic acid methyl ester which is a raw material is <1% in GC, 3-hydroxycyclobutane carboxylic acid methyl ester which is a cis-trans isomer of the compound 1 is 97.6% (trans/cis=55.3/44.7), 80mL of 30% NaOH solution is dropwise added at 20-30 ℃, after the dropwise addition, the temperature is kept for 5 hours, the GC is a compound 1<1%, isopropanol is concentrated under reduced pressure, 200mL of dichloromethane is added, 10% hydrochloric acid is dropwise added at 0-10 ℃ for pH=4-5, layering is carried out, a water layer is extracted for 2 times, 200mL of dichloromethane is combined each time, saturated salt is washed under reduced pressure, 100mL of n-heptane is filtered, and 42.5g of white compound is obtained after the organic layer is concentrated under reduced pressure, and the cis-trans-solid is 2.98.45% (2.45/6%) is obtained.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
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