CN112661687A - Synthesis method of (R) -3-hydroxypyrrolidine - Google Patents
Synthesis method of (R) -3-hydroxypyrrolidine Download PDFInfo
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- CN112661687A CN112661687A CN202011597880.7A CN202011597880A CN112661687A CN 112661687 A CN112661687 A CN 112661687A CN 202011597880 A CN202011597880 A CN 202011597880A CN 112661687 A CN112661687 A CN 112661687A
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- hydroxypyrrolidine
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- hydroxyproline
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- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 title claims abstract description 32
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 20
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012429 reaction media Substances 0.000 claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 7
- -1 methyl isobutyl Chemical group 0.000 claims abstract description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical group OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000000926 separation method Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 2
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 231100000252 nontoxic Toxicity 0.000 abstract description 3
- 230000003000 nontoxic effect Effects 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 10
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 229960002429 proline Drugs 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229930182821 L-proline Natural products 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 229940116298 l- malic acid Drugs 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- UQAVIASOPREUIT-VQIWEWKSSA-N darifenacin hydrobromide Chemical compound Br.C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 UQAVIASOPREUIT-VQIWEWKSSA-N 0.000 description 1
- 229960002287 darifenacin hydrobromide Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229950011346 panipenem Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
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- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing (R) -3-hydroxypyrrolidine, which comprises the steps of reacting L-hydroxyproline in a reaction medium under the action of a decarboxylation catalyst at 80-160 ℃, and distilling under reduced pressure to obtain (R) -3-hydroxypyrrolidine after the reaction is finished; the carboxylic acid decarboxylation catalyst is selected from methyl isobutyl or cyclohexanone. The synthesis method of (R) -3-hydroxypyrrolidine provided by the invention uses a cheap, safe and nontoxic decarboxylation catalyst and a reaction medium which is easier to recover, obtains a better yield than the prior art, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of (R) -3-hydroxypyrrolidine.
Background
The (R) -3-hydroxypyrrolidine is an important intermediate raw material for synthesizing panipenem and darifenacin hydrobromide. There are generally two methods for the synthesis of (R) -3-hydroxypyrrolidine: one method is that L-malic acid is used as initial material, and is first condensed with benzylamine, reduced, debenzylated and other steps reacted to obtain the product; another method is decarboxylation of L-hydroxyproline. The L-malic acid raw material is expensive, the synthesis steps are long, the production cost is high, the L-hydroxyproline is cheap and easy to obtain, and the synthesis steps are short. Decarboxylation of L-hydroxyproline is a more rational method for the large scale preparation of (R) -3-hydroxypyrrolidine.
The decarboxylation of L-hydroxyproline to produce (R) -3-hydroxypyrrolidine has been reported in the following documents:
U.S. Pat. No. 4, 5096890A discloses decarboxylation of L-hydroxyproline to produce 3-hydroxypyrrolidine with a yield of 51% using cyclohexanol as the reaction medium and 2-cyclohexen-1-one as the catalyst. Because the reaction product is relatively complex, the subsequent treatment needs to use a large amount of ethyl acetate and isopropanol for recrystallization after salification to obtain a high-purity product, and the post-treatment is relatively complex and the process cost is relatively high.
U.S. Pat. No. 4, 20050222430, 1 describes the decarboxylation of L-hydroxyproline to 3-hydroxypyrrolidine with PEG400 as the reaction medium and 2-cyclohexen-1-one as the catalyst, with a yield of 72.5%. Fei et al prepared 3-hydroxypyrrolidine by decarboxylation of L-hydroxyproline using PEG400 as a reaction medium and 2-cyclohexen-1-one as a catalyst at a yield of 76% (Fei, Lina, Dingjianha, Wang Yali, Guangzhou chemical (J),2017,45(17): 23-24).
The catalysts used in the method for preparing 3-hydroxypyrrolidine by decarboxylation of L-hydroxyproline reported in the above documents are all 2-cyclohexene-1-one, which has high price and is a highly toxic compound. Meanwhile, the reaction medium PEG400 in the report is a hydrophilic polymer substance which is mutually soluble with water, so that the recovery and the treatment are difficult, and the industrial production is not facilitated.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provided is a method for synthesizing (R) -3-hydroxypyrrolidine by using a less expensive, safe, non-toxic decarboxylation catalyst and a reaction medium which can be recovered more easily.
The technical scheme for solving the technical problems is as follows:
a method for synthesizing (R) -3-hydroxypyrrolidine comprises the following steps:
reacting L-hydroxyproline in a reaction medium at 80-160 ℃ under the action of a decarboxylation catalyst, and distilling under reduced pressure after the reaction is finished to obtain (R) -3-hydroxypyrrolidine;
the carboxylic acid decarboxylation catalyst is selected from methyl isobutyl or cyclohexanone.
Preferably, the reaction medium is selected from diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether or polyethylene glycol.
Preferably, the dosage of the reaction medium is 2-5 times of the mass of the L-hydroxyproline; furthermore, the dosage of the reaction medium is 2.2-4 times of the mass of the L-hydroxyproline.
Preferably, the amount of the carboxylic acid decarboxylation catalyst is 5-10% of the mass of the L-hydroxyproline; further, the amount of the carboxylic acid decarboxylation catalyst is 6-8% of the mass of the L-hydroxyproline.
Preferably, the reaction temperature is 140-160 ℃; further, the reaction temperature is 145-155 ℃.
Preferably, the reaction time of the reaction is 0.1-24 hours; further, the reaction time of the reaction is 2-10 hours; furthermore, the reaction time of the reaction is 4-8 hours.
Preferably, the reaction also comprises a water diversion operation, and the water diversion is carried out at 140-150 ℃.
Preferably, the temperature of the reduced pressure distillation is 60-70 ℃, and the pressure is 1000-2000 Pa.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The synthesis method of (R) -3-hydroxypyrrolidine provided by the invention uses a cheap, safe and nontoxic decarboxylation catalyst and a reaction medium which is easier to recover, obtains a better yield than the prior art, and is suitable for industrial large-scale production.
Drawings
FIG. 1 is a hydrogen spectrum of (R) -3-hydroxypyrrolidine obtained by the present embodiment.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
780g of diethylene glycol and methyl isobutyl ketone are added into a 2L four-neck flask with a water separator and a reflux condenser16.8g, adding 280g of L-proline while stirring, heating to 140 ℃ for water diversion, and continuously heating to 155 ℃; keeping the temperature for 8 hours until the solid is dissolved and clear, cooling to the internal temperature of about 60 ℃, connecting a thorn-shaped column, and distilling under reduced pressure to obtain light yellow liquid, namely (R) -3-hydroxypyrrolidine (157.8 g), the purity of which is 99.1 percent and the optical rotation [ a ]]D 25=-6.2o(C =3.5mg/mL, methanol solution), yield was 84.9%.
Example 2:
adding 280g of L-proline into a 2L four-neck flask with a water separator and a reflux condenser, stirring and adding 616g of diethylene glycol and 16.8g of cyclohexanone, heating to 145 ℃ for water separation, and continuously heating to 155 ℃; keeping the temperature for 6 hours, dissolving the solid clearly, cooling to the internal temperature of about 60 ℃, connecting a thorn-shaped column, and distilling under reduced pressure to obtain a light yellow liquid, namely (R) -3-hydroxypyrrolidine (152.5 g), the purity of which is 99.3 percent and the optical rotation [ a ]]D 25 = -6.4o(C =3.5mg/mL, methanol solution), the yield was 82.1%.
Example 3:
780g of diethylene glycol and 21.5g of methyl isobutyl ketone in a 2L four-neck flask with a water separator and a reflux condenser, adding 280g of L-proline while stirring, heating to 140 ℃ for water separation, and continuously heating to 155 ℃; keeping the temperature for 6 hours until the solid is dissolved and clear, cooling to the internal temperature of about 60 ℃, connecting a thorn-shaped column, and distilling under reduced pressure to obtain light yellow liquid, namely (R) -3-hydroxypyrrolidine (165.6 g), the purity of which is 99.0 percent and the optical rotation [ a ]]D 25 = -6.1o(C =3.5mg/mL, methanol solution), the yield was 89.2%.
Example 4:
8400g of diethylene glycol and 21.5g of cyclohexanone are added into a 2L four-neck flask with a water segregator and a reflux condenser pipe under stirring, 280g of L-proline is added, the temperature is increased to 150 ℃, water segregating is carried out, and the temperature is continuously increased to 155 ℃; keeping the temperature for 6 hours, dissolving the solid clearly, cooling to the internal temperature of about 65 ℃, connecting a thorn-shaped column, and distilling under reduced pressure to obtain light yellow liquid, namely (R) -3-hydroxypyrrolidine (155.6 g), the purity of which is 99.3 percent and the optical rotation [ a ]]D 25 = -6.4o(C =3.5mg/mL, methanol solution), yield was 83.8%.
Example 5:
in a 2.5L four-necked flask equipped with a water separator and a reflux condenser, 920g of diethylene glycol monomethyl ether and 21.5g of methyl isobutyl ketone were charged L under stirring280g of proline, heating to 140 ℃ for water diversion, and continuously heating to 155 ℃; keeping the temperature for 6 hours, dissolving the solid clearly, cooling to about 70 ℃ and connecting a thorn-shaped column for reduced pressure distillation to obtain light yellow liquid, namely (R) -3-hydroxypyrrolidine 159.6g, the purity is 99.6 percent and the optical rotation [ a ]]D 25=-6.5o(C =3.5mg/mL, methanol solution), yield 85.9%.
Example 6:
780g of diethylene glycol and 28.0g of methyl isobutyl ketone in a 2L four-neck flask with a water separator and a reflux condenser, adding 280g of L-proline while stirring, heating to 140 ℃ for water separation, and continuously heating to 155 ℃; keeping the temperature for 6 hours, dissolving the solid clearly, cooling to the internal temperature of about 60 ℃, connecting a thorn-shaped column, and distilling under reduced pressure to obtain light yellow liquid, namely (R) -3-hydroxypyrrolidine (165.8 g), the purity of which is 99.4 percent and the optical rotation [ a ]]D 25 =-6.3o(C =3.5mg/mL, methanol solution), the yield was 89.3%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A method for synthesizing (R) -3-hydroxypyrrolidine is characterized by comprising the following steps:
reacting L-hydroxyproline in a reaction medium at 80-160 ℃ under the action of a decarboxylation catalyst, and distilling under reduced pressure after the reaction is finished to obtain (R) -3-hydroxypyrrolidine;
the carboxylic acid decarboxylation catalyst is selected from methyl isobutyl or cyclohexanone.
2. The method of synthesizing (R) -3-hydroxypyrrolidine according to claim 1, wherein the reaction medium is selected from diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, or polyethylene glycol.
3. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 1, wherein the amount of the reaction medium is 2-5 times the mass of L-hydroxyproline.
4. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 3, wherein the amount of the reaction medium is 2.2-4 times the mass of L-hydroxyproline.
5. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 1, wherein the amount of the carboxylic acid decarboxylation catalyst is 5 to 10% by mass of L-hydroxyproline.
6. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 5, wherein the amount of the carboxylic acid decarboxylation catalyst is 6-8% by mass of L-hydroxyproline.
7. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 1, wherein the reaction temperature is 140-160 ℃.
8. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 1, wherein the reaction time is 0.1 to 24 hours.
9. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 1, wherein the reaction further comprises a water separation operation, and the water separation is performed at 140-150 ℃.
10. The method for synthesizing (R) -3-hydroxypyrrolidine according to claim 1, wherein the temperature of the reduced pressure distillation is 60 to 70 ℃ and the pressure is 1000 to 2000 Pa.
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