CN104263795A - Method for preparing chiral alpha-naphthenic glycine - Google Patents
Method for preparing chiral alpha-naphthenic glycine Download PDFInfo
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Abstract
A method for preparing chiral alpha-naphthenic glycine adopts glycine as a starting material to prepare chiral alpha-naphthenic glycine of which the enantiomeric purity (ee%) is greater than 99% through esterification, condensation, substitution, deprotection, acylation and enzymatic resolution. Naphthenic base is cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. The method adopts low-price easily-accessible raw materials, and is stable in process, simple to implement and environment-friendly, and achieves the reaction total recovery of 46-54%; the enzymatic resolution is adopted, so that the enzyme consumption is low, the using amount of L-acylase is 0.2% of that of a substrate, the using amount of D-acylase is 0.005% of that of the substrate, and the optical purity of the prepared chiral alpha-naphthenic glycine is greater than 99%; a new concept and a new method are provided for large-scale production and deepening of the glycine industrial chain.
Description
Technical field
The present invention relates to amino acid whose synthetic method, particularly a kind of method preparing chiral alpha-cycloalkyl glycine.
Background technology
Hepatitis C (HCV) is the worldwide disease of one caused by hepatitis C virus.Mainly through blood transfusion or blood product, Hemodialysis, Plasma Pheresis/Apheresis Plasma also transfuse blood ball, renal transplantation, intravenous injection drug use, spread through sex intercourse and the route infection such as parent.At the beginning of virus infection, symptom is slight or do not have symptom, transfer to chronic after, majority do not have symptom in long-time yet, the infected of nearly 65-70% does not know to carry hepatitis C virus in their health usually, and therefore the third liver is called as " noiseless liver killer ".
Hepatitis C is distributed more widely, and within 2009, there is the third hepatopath 1.8 hundred million in the whole world, is 4 times of patients infected hiv, is the transmissible disease of global mortality ratio the tenth, and becomes in world wide the primary cause of disease accepting liver transplantation.It is predicted, the market share to global HCV in 2016 will reach 8,000,000,000 ~ 10,000,000,000 dollars.
Chiralα-aminoacid is the important intermediate of improvement on synthesis and lactam drugs, is widely used in the fields such as medicine synthesis, pesticide synthesis, foodstuff additive, feed, novel material synthesis and fine chemicals.Chiralα-aminoacid comprises L-a-amino acid and D-a-amino acid, comprises huge number, as 20 kinds of natural amino acids are L-a-amino acid.Chiral alpha-cycloalkyl glycine then belongs to chiralα-aminoacid, its constitutive characteristic is the alpha-position of its glycine is that cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) replaces, and comprises L-α-cycloalkyl glycine and D-α-cycloalkyl glycine.Chiral alpha-cycloalkyl glycine is widely used in much important this enzyme of albumen production agent and the synthesis, the particularly synthesis of hepatitis C medicine of other chiral medicinal intermediate.Wherein L-α-cyclopentylglycine is the important intermediate of synthesizing multiple third liver kind new medicine, L-α-Cyclohexylglycine is the important intermediate such as synthesis third liver class medicine VX-960, MK-1220, and D-α-cyclopentylglycine is the important intermediate of kinases (JAK) inhibitor and hyperlipidemia inhibitor.Therefore, the synthesis of such chipal compounds has very large marketable value.
The method preparing chipal compounds mainly comprises Split Method and dissymmetric synthesis.Current preparation D or L-α-cycloalkyl glycine compounds main method is dissymmetric synthesis and Split Method, specific as follows:
1, document Tetrah.Lett., 2003,44,2683 – 2685; J.Amer.Chem.Soc., 1988,110 (5), 1547-57 etc. report and prepare chiral alpha-cycloalkyl glycine method with chirality glycine enol Equivalent cycloalkyl substituted.This method is with (1R, 2S)-2-amino-1,2-phenylbenzene ethanol, bromacetate and Cbz-Cl etc. are prepared into chirality glycine enol Equivalent for raw material, and then with cycloalkyl iodine or its Equivalent alkylation after, then obtain chirality L-α-cyclopentylglycine by hydrogenolysis deprotection; The program wants reactions steps longer; (the 1R using price high is needed in technique; 2S)-2-amino-1; 2-phenylbenzene ethanol is auxiliary material; reduce with noble metal catalyst; in addition, LiHMDS highly basic need be adopted when cyclopentyl builds to use at profound hypothermia conditioned disjunction the silane reagent that price is high, be unfavorable for large-scale production.
2, document J.Org.Chem.1999,64,2276-2280 report the method preparing chiral alpha-cycloalkyl glycine with unsaturated 2-aza-bicyclo compound hydrogenolysis.This method for main raw material, obtains D or L-α-cycloalkyl glycine through the polystep reaction such as cyclization, hydrogenolysis with glyoxylic ester, (R)-or (S)-α-phenylethylamine, cyclopentadiene etc.; The program seems simple, and be only 2-3 step, but technological process complicated operation, need profound hypothermia to react, noble metal catalyst need be used to carry out hydrogenolysis reducing, and cost is high, is not suitable for large-scale production.
3, document Chem.Commun., 2002,246-247 report and prepare L-α-cyclopentylglycine with the method for pig kidney D-AAO fractionation.With DL-α-cyclopentylglycine for raw material, pig kidney D-AAO, in conjunction with catalase, prepares L-α-cyclopentylglycine.Although the yield of reported in literature high (79%), but pig kidney D-AAO price high (259 yuan/mg, 2u/mg) and consumption large (5u/L), also need the sodium borohydride using 3 equivalents simultaneously, cost is high, does not still possess scale production meaning at present.
4, document J.Biol.Chem.1954,206,401-410 then report the preparation method of DL-α-cyclopentylglycine.The method for starting raw material, obtains DL-α-cyclopentylglycine with 5 steps such as alkylation, bromo, hydrolysis, decarboxylation, ammonia solutions with diethyl malonate, bromocyclopentane; The method uses low in raw material price, but yield is very low, and production cost is very high, is not suitable for large-scale production.
Therefore, for solving the difficult problem existed in prior art, starting material need be found to be easy to get, with low cost, technique is simple, and yield and optical purity are all higher, and is applicable to the synthetic route of large-scale production L-or D-α-cycloalkyl glycine.
Summary of the invention
The object of the present invention is to provide a kind of method taking glycine as raw material and prepare racemization α-cycloalkyl glycine, chiral alpha-cycloalkyl glycine or its hydrochloride, the method desired raw material is cheap and easy to get, and process stabilizing is simple to operate, and reaction yield is high; Particularly adopt enzymatic resolution method, prepare chiral alpha-cycloalkyl glycine that optical purity is greater than 99%; For large-scale production and in-depth glycine industrial chain provide a kind of new approaches and method.
Chiral alpha of the present invention-cycloalkyl glycine or its hydrochloride structural formula are such as formula (I ~ II):
Wherein n=1,2,3,4.
Technical scheme of the present invention is as follows, and its operational path is:
Concrete steps are:
(1), be starting raw material with glycine, esterification obtains tert-butyl glycinate;
(2), by tert-butyl glycinate and benzophenone being dissolved in varsol, take tosic acid as catalyzer, and condensation obtains N-diphenylmethylene tert-butyl glycinate;
(3), N-diphenylmethylene tert-butyl glycinate and halo naphthenic hydrocarbon are dissolved in ether solvent, under basic conditions, replace obtained N-diphenylmethylene-α-cycloalkyl tert-butyl glycinate;
(4), N-diphenylmethylene-α-cycloalkyl tert-butyl glycinate deprotection in strong acid system, obtained DL-α-cycloalkyl glycine or DL-α-cycloalkyl glycine hydrochloride;
(5), DL-α-cycloalkyl glycine or DL-α-cycloalkyl glycine hydrochloride be dissolved in solvent, acidylate in the basic conditions, obtained N-ethanoyl-DL-α-cycloalkyl glycine;
(6), with enzyme catalysis N-ethanoyl-DL-α-cycloalkyl glycine, obtained chirality L-α-cycloalkyl glycine or chiral D-α-cycloalkyl glycine is split.
Varsol described in step (2) is selected from one of toluene, dimethylbenzene, normal hexane, hexanaphthene or any several mixture in them, is preferably toluene; The preferred 110-120 DEG C of temperature of reaction.
In step (3), the halogen of halo naphthenic hydrocarbon is selected from one of Cl, Br, I, OTs, OMs, one of preferred Br, Oms, OTs; Described ether solvent is one of tetrahydrofuran (THF), ether, methyl tertiary butyl ether, isopropyl ether, preferred tetrahydrofuran (THF); Described highly basic is one of potassium tert.-butoxide, sodium tert-butoxide, sodium hydride, preferred potassium tert.-butoxide or sodium tert-butoxide.
Described in step (4), strong acid is trifluoroacetic acid or hydrochloric acid.
In step (5), acylating reagent is one of diacetyl oxide, Acetyl Chloride 98Min., propionyl chloride, Benzoyl chloride, phenyllacetyl chloride, preferred diacetyl oxide or phenyllacetyl chloride; Alkali used is one of sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, triethylamine, preferred sodium hydroxide; Reaction solvent preferably water.
Enzyme in step (6) is D-acylase or L-acylase, reaction solvent preferably water; PH is 7 ~ 8, preferably 7 ~ 7.5.
Beneficial effect of the present invention:
Take tert-butyl glycinate as starting raw material, reacted by a few step, with higher yields, obtain chiral alpha-cycloalkyl glycine high-optical-purity; The raw material used in technique is easy to get, cheap; It is little, simple to operate that enzyme splits consumption, is applicable to large-scale production completely.Process overall yields about 50%, products obtained therefrom optical purity ee>99%; And optionally obtain L-or D-form.
Embodiment
Now further illustrate the present invention by following examples, but protection scope of the present invention is not limited only to this.
Embodiment 1 prepares L-α-cyclopentylglycine (in formula I n=3):
(1) esterification
The tert-butyl glycinate used in the present invention or its hydrochloride adopt patent in early stage (CN201310083350.4) technology of applicant to prepare, and method is:
1400L tert.-butyl acetate is added in the reactor of 2000L, 105kg glycine, at the uniform velocity drip 180kg perchloric acid, about 48-72 hour is reacted in 0-10 DEG C, TLC monitoring reaction to glycine reactant transformation efficiency more than 90% after stopped reaction, adjust pH for 6.5-7.5 with 4mol/L sodium hydroxide, separate organic layer, water layer continuation tert.-butyl acetate to extract in straight aqueous phase product lower than after 5%, merge organic phase gas producing formation, after salt water washing is pure to product TLC, obtain the tert.-butyl acetate solution of 1500L tert-butyl glycinate; Concentration and recovery tert.-butyl acetate obtains tert-butyl glycinate 180kg.
(2) condensation:
Toluene 160L is added successively in 300L reactor, benzophenone 18.2kg (1.0eq.), tert-butyl glycinate 15.7kg (1.2eq.), tosic acid monohydrate 2.06kg (0.12eq.), be warming up to 115 ± 5 DEG C of reactions under stirring; Divisor divides water, lowers the temperature after completion of the reaction, suction cold water washing 2 times (80L*2), and organic phase concentrates, formula III compound N-diphenylmethylene tert-butyl glycinate 26.6kg, yield 90.4%, HPLC:90.3%.
(3) substitution reaction:
Tetrahydrofuran (THF) 45L is added in 100L reactor, potassium tert.-butoxide 3.3kg, be cooled to-5 ± 5 DEG C, drip and be dissolved in by 6kg N-diphenylmethylene tert-butyl glycinate the solution that 15L tetrahydrofuran (THF) formed, drip ratio, stir after 1 hour, drip bromocyclopentane 4.2kg, drip finish, maintains-5 ± 5 DEG C reaction 1 hour, after be warmed up to 20 DEG C react 5 hours; React complete, add 20L water termination reaction, concentrate after removing tetrahydrofuran (THF), add extraction into ethyl acetate (20L × 2); Merge organic phase, concentrate to obtain formula (V) compound N-diphenylmethylene-α-cyclopentylglycine tert-butyl ester 6.45kg, yield 87.3%, HPLC:91.6%.
(4) deprotection:
N-diphenylmethylene-α-cyclopentylglycine tert-butyl ester 18kg is added in 100L reactor, add 6N hydrochloric acid 60L, reflux 8 hours, after having reacted, cooling, dichloromethane extraction 2 times (20L × 2), aqueous phase is concentrated into dry formula VI Compound D L-α-cyclopentylglycine hydrochloride 7.19kg; Yield 81%.
(5) acetylize:
DL-α-cyclopentylglycine hydrochloride 17.96kg is added in 200L reactor; add 2.5mol/L NaOH 140L; stir lower aceticanhydride 13.3L, react 10 hours under normal temperature, after having reacted; about pH=2 is adjusted with 6N hydrochloric acid; stirring and crystallizing, centrifugal rejection filter, obtains formula (VII) compound N-acetyl-α-cyclopentylglycine crystal 17.7kg; yield 95.7%, HPLC 99.5%.
(6) enzyme splits preparation L-α-cyclopentylglycine:
In 500L reactor, add 400L pure water, N-ethanoyl-α-cyclopentylglycine 10kg, ammoniacal liquor adjusts pH to be 7.0-7.5, and temperature control about 37 DEG C, adds L-acylase 25 grams, reacts 24 hours, after reacting completely, filters, except mechanical impurity and enzyme; Reaction solution proceeds in 500L still, and tune pH is about 3-4, adds extraction into ethyl acetate (100L × 2), organic phase concentration and recovery N-ethanoyl-D-α-cyclopentylglycine 5.2kg, for subsequent use; It is 10-20L that aqueous phase is concentrated into system volume, cooling crystallization, and suction filtration obtains formula I compound L-α-cyclopentylglycine 3.29kg, yield 85%, HPLC 99.4%, ee value 99.6%.
1HNMR(400MHz，DMSO-d
6):δ8.52(3H,s),3.72(1H,m),2.24(1H,m),1.72(2H,m),1.59(2H,m),1.53–1.45(3H,m),1.43–1.34(1H,m)；
ESIMS：144.3[M+H]
+
Embodiment 2: preparation D-α-cyclopentylglycine (in formula I n=3):
(1) DL-α-cyclopentylglycine hydrochloride is as the preparation of example 1 method;
(2) enzyme splits: in 200L reactor, add 100L phosphate buffer solution; 5.2kgDL-α-cyclopentylglycine hydrochloride; pH7.8-8.2 is adjusted with sodium hydroxide; constant volume is 130L; reaction system is warming up to 38 ~ 42 DEG C and is incubated; add D-acylase 0.26g, stirring reaction 24 hours.PH is adjusted to be about 3 with hydrochloric acid, extraction into ethyl acetate (50L × 2); Aqueous phase adjusts pH to be about 5.5, and being evaporated to volume is 10-20L, now has solid to separate out, crystallisation by cooling, suction filtration, obtains white solid formula II chiral D-α-cyclopentylglycine 3.40kg, yield 88%; HPLC 99.0%, ee value 99.4%.
1HNMR(400MHz，DMSO-d
6):δ8.50(3H,s),3.71(1H,m),2.22(1H,m),1.73(2H,m),1.58(2H,m),1.54–1.47(3H,m),1.45–1.34(1H,m)；
ESIMS：144.2[M+H]
+
Embodiment 3: preparation L-α-Cyclohexylglycine (in formula I n=4):
(1) substitution reaction:
Tetrahydrofuran (THF) 45L is added in 100L reactor, potassium tert.-butoxide 3.3kg, be cooled to-5 ± 5 DEG C, drip and be dissolved in by 6 kgN-diphenylmethylene tert-butyl glycinates the solution that 15L tetrahydrofuran (THF) formed, finish, stir after 1 hour, drip cyclohexyl bromide 4.6kg, drip finish, maintains-5 ± 5 DEG C reaction 1 hour, after be warmed up to 20 DEG C react 5 hours; React complete, add 20L water termination reaction, concentrate after removing tetrahydrofuran (THF), add extraction into ethyl acetate (20L × 2); Merge organic phase, concentrate to obtain N-diphenylmethylene-DL-α-Cyclohexylglycine tert-butyl ester 6.6kg, yield 86%, HPLC:91.0%.(2) deprotection:
N-diphenylmethylene-DL-α-Cyclohexylglycine tert-butyl ester 18.7kg is added in 100L reactor, add 6N hydrochloric acid 65L, reflux 9 hours, after having reacted, cooling, dichloromethane extraction 2 times (25L × 2), aqueous phase is concentrated into dry formula VI Compound D L-α-Cyclohexylglycine hydrochloride 7.86kg; Yield 82%.
(3) acetylize:
DL-α-Cyclohexylglycine hydrochloride 9.68kg is added in 200L reactor; add 2.5mol/L NaOH 70L; stir lower aceticanhydride 6.65L, react 8 hours under normal temperature, after having reacted; about pH=2 is adjusted with 6N hydrochloric acid; stirring and crystallizing, centrifugal rejection filter, obtains formula (VII) compound N-acetyl-DL-α-Cyclohexylglycine crystal 9.3kg; yield 93.5%, HPLC 99.3%.
(4) enzyme splits preparation L-α-Cyclohexylglycine:
In 500L reactor, add 400L pure water, N-ethanoyl-DL-α-Cyclohexylglycine 10kg, ammoniacal liquor adjusts pH to be 7.0-7.5, and temperature control about 37 DEG C, adds L-acylase 20 grams, reacts 24 hours, after reacting completely, filters, except mechanical impurity and enzyme; Reaction solution proceeds in 500L still, and tune pH is about 3-4, adds extraction into ethyl acetate (100L × 2), organic phase concentration and recovery N-ethanoyl-D-α-Cyclohexylglycine 5.1kg, for subsequent use; It is 15-25L that aqueous phase is concentrated into system volume, cooling crystallization, and suction filtration obtains formula (I) compound L-α-Cyclohexylglycine 3.39kg, yield 86%, HPLC 99.4%, ee value 99.5%.
1HNMR(400MHz，D
2O):δ3.34(d,J＝5.4,1H),0.54-1.20(m,11H)；ESIMS：158.2[M+H]
+?。
Claims (10)
1. prepare a method for chiral alpha-cycloalkyl glycine, comprise step:
(1), be starting raw material with glycine, esterification obtains tert-butyl glycinate;
(2), being dissolved in varsol by tert-butyl glycinate and benzophenone, take tosic acid as catalyzer, and condensation obtains N-diphenylmethylene tert-butyl glycinate;
(3), N-diphenylmethylene tert-butyl glycinate and halo naphthenic hydrocarbon are dissolved in ether solvent, under basic conditions, replace obtained N-diphenylmethylene-α-cycloalkyl tert-butyl glycinate;
(4), N-diphenylmethylene-α-cycloalkyl tert-butyl glycinate deprotection in strong acid system, obtained DL-α-cycloalkyl glycine or DL-α-cycloalkyl glycine hydrochloride;
(5), DL-α-cycloalkyl glycine or DL-α-cycloalkyl glycine hydrochloride be dissolved in solvent, acidylate in the basic conditions, obtained N-ethanoyl-DL-α-cycloalkyl glycine;
(6), with enzyme catalysis N-ethanoyl-DL-α-cycloalkyl glycine, obtained chirality L-α-cycloalkyl glycine or chiral D-α-cycloalkyl glycine is split.
2. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 1, it is characterized in that, varsol described in step (2) is selected from one of toluene, dimethylbenzene, normal hexane, hexanaphthene or any several mixture in them; The preferred 110-120 DEG C of temperature of reaction.
3. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 1, it is characterized in that, in step (3), the halogen of halo naphthenic hydrocarbon is selected from one of Cl, Br, I, OTs, OMs; Described ether solvent is one of tetrahydrofuran (THF), ether, methyl tertiary butyl ether, isopropyl ether; Described highly basic is one of potassium tert.-butoxide, sodium tert-butoxide, sodium hydride.
4. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 1, it is characterized in that, described in step (4), strong acid is trifluoroacetic acid or hydrochloric acid.
5. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 1, it is characterized in that, in step (5), acylating reagent is one of diacetyl oxide, Acetyl Chloride 98Min., propionyl chloride, Benzoyl chloride, phenyllacetyl chloride; Alkali used is one of sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, triethylamine; Reaction solvent preferably water.
6. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 1, it is characterized in that, the enzyme in step (6) is D-acylase or L-acylase, reaction solvent preferably water; PH is 7 ~ 8.
7. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 2, it is characterized in that, described varsol is toluene.
8. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 3, it is characterized in that, the halogen of described halo naphthenic hydrocarbon is one of Br, OMs, OTs; Described ether solvent is tetrahydrofuran (THF); Described highly basic is potassium tert.-butoxide or sodium tert-butoxide.
9. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 5, it is characterized in that, described acylating reagent is diacetyl oxide or phenyllacetyl chloride; Alkali used is sodium hydroxide.
10. prepare the method for chiral alpha-cycloalkyl glycine as claimed in claim 6, it is characterized in that, described pH is 7 ~ 7.5.
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| CN106399412A (en) * | 2016-06-03 | 2017-02-15 | 南京红杉生物科技有限公司 | Method for synthesizing D-biphenyl alanine |
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| CN106399412B (en) * | 2016-06-03 | 2019-12-10 | 南京红杉生物科技有限公司 | Method for synthesizing D-biphenylalanine |
| CN115073314A (en) * | 2022-07-11 | 2022-09-20 | 吉尔多肽生物制药(大连市)有限公司 | Synthesis method of secondary carbon glycine |
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Application publication date: 20150107 |