CN107474107A - GLYX 13 preparation method and the compound for preparing GLYX 13 - Google Patents
GLYX 13 preparation method and the compound for preparing GLYX 13 Download PDFInfo
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- CN107474107A CN107474107A CN201710355328.9A CN201710355328A CN107474107A CN 107474107 A CN107474107 A CN 107474107A CN 201710355328 A CN201710355328 A CN 201710355328A CN 107474107 A CN107474107 A CN 107474107A
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- 0 C*1N(*)CCC1 Chemical compound C*1N(*)CCC1 0.000 description 8
- NQGVPJOLHMMARB-RUYJGKKWSA-N C=C/C=C(/COC([C@H]1NCCC1)=O)\C=C Chemical compound C=C/C=C(/COC([C@H]1NCCC1)=O)\C=C NQGVPJOLHMMARB-RUYJGKKWSA-N 0.000 description 1
- ISWLSTFSKLMIQA-UHFFFAOYSA-N CC(C(C(N)=O)NC)O Chemical compound CC(C(C(N)=O)NC)O ISWLSTFSKLMIQA-UHFFFAOYSA-N 0.000 description 1
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
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- 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
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Abstract
The invention belongs to pharmaceutical compound field, there is provided the preparation method of GLYX 13 a kind of and the compound for preparing GLYX 13.Method provided by the invention is using Fmoc O tert-butyl group L threonines, Fmoc L proline, N benzyloxycarbonyl groups L threonyls amine and proline benzyl ester hydrochloride as initiation material; use the synthetic method of the present invention; it can easily be carried out by eight steps and the synthesis step of economy in commercial quantity prepares GLYX 13 with higher yield; simple technological operation can be passed through to prepare with good yield and relatively low cost, malicious or strong corrosivity deprotecting regent is easily made without the peptide condensation reagent using costliness and by control.
Description
Technical field
The invention belongs to pharmaceutical compound field, there is provided a kind of GLYX-13 preparation method and for preparing GLYX-13
Compound.
Background technology
Rapastinel (GLYX-13) is the new antidepression candidate developed by small-sized biological technology company of U.S. Naurex
Medicine, it is N-methyl-D-aspartate receptor glycine site partial agonist, structure is as follows, is that a tetrapeptide derives
Thing, it is highly soluble in water.The quick of U.S. FDA is obtained because it shows the antidepressant effect of quick acting early stage in research and development
Passage is examined, and has been enter into third stage conceptual phase at present.
GLYX-13 synthesising process research is disclosed in CN104109189A, the route is revived with the Fmoc-O- tert-butyl groups-L-
Propylhomoserin, Fmoc- proline and proline methyl ester hydrochloride are initiation material, the use of isobutyl chlorocarbonate are condensation reagent, are passed through
The reaction of totally nine steps synthesizes GLYX-13 for the ammonolysis reaction of carboxylic acid, three times peptide condensation reaction and five Deprotections.
But the route has the disadvantage that：
1. intermediate IV also is difficult to obtain, yield is low, even if it is also grease to obtain, it has not been convenient to which the next step feeds intake.
2. the synthesis yield of intermediate V is low, reaction is incomplete, has the accessory substance for being difficult to remove, main cause is unsuitable
Method of condensing isobutyl chlorocarbonate IBCF, and used raw material proline methyl ester hydrochloride hygroscopicity is extremely strong, it has not been convenient to throws
Material operation.
3. not considering the compatibility between different protection groups in the building-up process of intermediate VI, Fmoc protection groups can react
During removing cause the yield of intermediate VI extremely low.
4. although the method for de- Fmoc protection groups is classical, to be studied to amplify applied to technique, feasibility is very poor, because
DMF and piperidines boiling point high viscosity are difficult to eliminate greatly, have apparent influence to peptide condensation reaction below, and piperidines is easily to make
Poison is not easy to buy by controlled drug.
5. the method that intermediate VIII takes off the tert-butyl group is also very classical, reagent is trifluoroacetic acid, but the corrosion of trifluoroacetic acid
Property it is strong, volatile and toxicity is big, be not suitable for industrialized production, post processing be not easy to eliminate.
6. the end-product that this route obtains is GLYX-13 trifluoroacetate salt, it is necessary to can just be obtained by dissociation
GLYX-13。
The content of the invention
Compound it is an object of the invention to provide the preparation method of GLYX-13 a kind of and for preparing GLYX-13, with gram
Take drawbacks described above existing for prior art.
The present invention provides following technical scheme to solve the above problems：
On the one hand, the present invention provides a kind of GLYX-13 preparation method, it is characterised in that described Formula VII compound exists
In organic solvent, under deprotecting regent effect, Fmoc protection groups are removed, prepare GLYX-13, reaction equation is as follows：
Described deprotecting regent is TBA and n-octyl mercaptan；Organic solvent be selected from methanol, ethanol, dichloromethane, DMSO,
One or more in DMF, preferably dichloromethane.
Further, the preparation method of described Formula VII compound includes：
Step 1) is in aprotic polar organic solvent, in the presence of condensing agent, alkali, formula III and Formula V reaction formula VIization
Compound；；
Step 2) Formula IV compound further in organic solvent, under deprotecting regent effect, protect by the removing tert-butyl group
Base, formula VII compound reaction equations are as follows：
In the preparation method of above-mentioned Formula VII, the non-proton organic solvent described in described step 1) is selected from acetonitrile, four
One or more in hydrogen furans, dichloromethane, DMF, preferably DMF；Described condensing agent is selected from EDCI, tolysulfonyl
One or more in chlorine, Cyanuric Chloride, pivaloyl chloride, condensing agent are preferably pivaloyl chloride；Described alkali is selected from N- methyl
One or more in quinoline, triethylamine, N- methylimidazoles, DIPEA, imidazoles, described alkali are preferably imidazoles；
The one kind of deprotecting regent in 85% phosphate aqueous solution, sodium iodide/cerous chloride and zinc bromide in described step 2)
Or several, preferably zinc bromide；Described solvent is in dichloromethane, methanol, ethyl acetate, methyl acetate, Ethyl formate
One or more, preferably ethyl acetate.
Further, Formula II compound room temperature under conditions of deprotecting regent and organic solvent removes Fmoc protection groups,
Compound of Formula III is prepared, reaction equation is as follows：
In the preparation method of above-mentioned formula III compound, described deprotecting regent is diethylamine, alchlor, dimethyl
Sulfoxide (DMSO) and the tert-butyl alcohol (TBA)/n-octyl mercaptan etc., preferably TBA/ n-octyl mercaptans；The solvent is methanol, ethanol, first
Benzene and TBA, preferably TBA.
Further, described Formula V compound includes following reactions steps：
Step 1), the Fmoc-O- tert-butyl groups-L-threonine and proline benzyl ester hydrochloride in organic solvent, condensing agent,
Intermediate IV is generated under the conditions of alkali alkali is existing；
Step 2), intermediate IV make catalyst, triethyl silicane as hydrogen donor high selectivity using palladium carbon in organic solvent
Remove benzyl ester protection group formula V compounds；
Reaction equation is as follows：
Further, in above-mentioned formula compound V preparation method, condensation reagent in described step 1) is EDCI, right
Toluene sulfochloride, Cyanuric Chloride and pivaloyl chloride, preferably pivaloyl chloride；The alkali is N-methylmorpholine, triethylamine, N- methyl
Imidazoles, DIPEA and imidazoles, preferably imidazoles；The organic solvent is tetrahydrofuran, acetonitrile, N, N- dimethyl methyls
Acid amides (DMF) and dichloromethane etc., the preferably mixed solvent of tetrahydrofuran and dichloromethane；Hydrogen in described step 2) supplies
Body is formic acid, ammonium formate, hydrogen and triethyl silicane, preferably triethyl silicane；The organic solvent be selected from methanol, ethanol,
One or more in tetrahydrofuran, ethyl acetate；Preferably ethanol.
Further, using N- benzyloxycarbonyl group-L- threonyls amine as initiation material, Cbz protection groups are sloughed by catalytic hydrogenation,
Formula II compounds, including following reactions steps are condensed with Fmoc-L- proline：
Step 1), N- benzyloxycarbonyl group-L- threonyls amine hydrogenate deprotection base benzyloxycarbonyl group under palladium carbon catalytic condition；
Step 2), Fmoc-L- proline and type I compound generate by condensing agent of isobutyl chlorocarbonate in organic solvent
The compound of formula II；One or more of the solvent in tetrahydrofuran, acetonitrile, dichloromethane or DMF, preferred solvent are
DMF；
Described Formula II compound is prepared by following reaction：
On the other hand, the present invention provides formula III compound, Formula IV compound, VII compounds noval chemical compound and is used to prepare
GLYX-13：
General technology scheme of the present invention：
In experimentation it was found that with the Fmoc-O- tert-butyl groups-L-threonine, Fmoc-L- proline, N- benzyloxy carbonyls
Base-L- threonyls amine and proline benzyl ester hydrochloride are initiation material, using the synthetic method of the present invention, can be held by eight steps
Easily carry out and the synthesis step of economy in commercial quantity prepares GLYX-13 with higher yield.
The advantageous effects of the present invention：
The present invention provides the side for preparing GLYX-13 and its key intermediate that a kind of safety and commercial scale are easily controlled
Method, simple technological operation can be passed through by this method and prepared with good yield and relatively low cost, without using
Expensive peptide condensation reagent and poison is easily made by control or the strong deprotecting regent of corrosivity, compound of formula VTI of the present invention pass through
De- Fmoc reactions can directly obtain GLYX-13, avoid into that to dissociate the cumbersome and yield reduction brought etc. again after salt potential
Problem.It is embodied in the following aspects：
1), the preparation post processing of intermediate II is extremely simple, only water need to be added into reaction solution and appropriate second is slowly added dropwise
Acetoacetic ester, so that it may obtain the very high intermediate II of purity.
2), deprotecting regent tert-butylamine and n-octyl mercaptan used in intermediate III and GLYX-13 preparation are cheap and easy to get,
Only 46 DEG C of tert-butylamine low boiling point, accessory substance is easy to remove.
3) the condensation reagent pivaloyl chloride, used in the preparation of intermediate IV and intermediate VI is cheap, in reaction
There is no an accessory substance generation, yield is higher.
4), the reaction of debenzylation used in the preparation of intermediate V protection based method is gentle, and Fmoc is resistance to this reaction condition
By can be with higher yields selectively removing benzyl protecting group.
5) zinc bromide used in the preparation of intermediate VII is compared with traditional de- tert-butyl group protection reagent trifluoroacetic acid
One less toxic reagent.Importantly, intermediate VII and intermediate V, the dissolubility of intermediate VI are widely different so that separation
Purifying becomes very simple, and intermediate VII is easy to crystallize out from reactant mixture, and purity is very good, without related intermediate
Impurity remains.
Embodiment
The present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment below.
Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, and these improvement also should be regarded as
Protection scope of the present invention.
In following embodiments, unless otherwise indicated, described experimental method is generally built according to normal condition or manufacturer
The condition of view is implemented；Shown raw material, reagent can be obtained by way of commercially available purchase.
The preparation of the intermediate I of embodiment 1
N-Cbz-L- threonyls amine (2mol, 504g), palladium carbon (50.4g) are added into 5L autoclave and without water beetle
Alcohol 3000mL, mechanical agitation make N-Cbz-L- threonyl amine solvents, are passed through hydrogen to reactor and maintain pressure 1MPa, room temperature
React 12h.Palladium carbon is removed by filtration after completion of the reaction, and filtrate removes solvent with rotary evaporator and obtains the thick of light yellow oil
Product.With 2L acetone solution crude products, the aqueous isopropanol of hydrogen chloride is added dropwise under the conditions of ice-water bath, separates out white solid, filters simultaneously
Vacuum drying can obtain white solid powder 289g, yield：93%.1H NMR(400MHz,D2O) δ 4.15 (p, J=6.1Hz,
1H), 3.86 (d, J=5.2Hz, 1H), 1.25 (d, J=6.5Hz, 3H) .HRMS (ESI-TOF+) m/z Calcd.for
C4H11N2O2 +[M+H]+:119.0815,found 119.0817。
The preparation of the intermediate II of embodiment 2
Embodiment 2.1
N-Fmoc- proline (1.5mol, 505g) is added to a 3L four-hole boiling flask, is added under conditions of nitrogen stream
1500mL dry DMFs, mechanical agitation are allowed to dissolve and add N-methylmorpholine (152g), reaction bulb bottom is in low-temp reaction
In device, the temperature that isobutyl chlorocarbonate (205g) and maintenance reaction liquid is slowly added dropwise is less than -15 DEG C, with solid shape after being added dropwise
Formula adds intermediate I (243g), and N-methylmorpholine (152g) is then slowly added dropwise, reaction solution is gradually returned to room after being added dropwise
Temperature.Reaction solution is transferred in Plastic Drum and adds purified water (9L), then is added dropwise thereto under conditions of mechanical agitation
1500mL ethyl acetate, there is white solid precipitation, filter and be dried in vacuo and to obtain white solid 585g, yield：89.2%.1H NMR
(400MHz,DMSO-d6) δ 7.98-7.56 (m, 5H), 7.50-7.29 (m, 4H), 7.14 (m, 2H), 4.86 (dd, J=18.2,
5.3Hz,1H),4.58–4.13(m,4H),4.13–3.94(m,2H),3.56–3.36(m,2H),2.31–1.76(m,4H),
1.00 (dd, J=14.9,6.3Hz, 3H) .HRMS (ESI-TOF+)m/z Calcd.for C24H27N3O5 +[M+H]+:
438.4960,found 438.2026。
Embodiment 2.2
N-Fmoc- proline (1.5mol, 505g) is added to a 3L four-hole boiling flask, 3L is added under conditions of nitrogen stream
Anhydrous tetrahydro furan, mechanical agitation are allowed to dissolve and add N-methylmorpholine (152g), reaction bulb bottom is in low-temp reaction
In device, the temperature that isobutyl chlorocarbonate (205g) and maintenance reaction liquid is slowly added dropwise is less than -15 DEG C, with solid shape after being added dropwise
Formula adds intermediate I (243g), and N-methylmorpholine (152g) is then slowly added dropwise, reaction solution is gradually returned to room after being added dropwise
Temperature.Reaction solution is transferred in Plastic Drum and adds purified water (9L), then is added dropwise thereto under conditions of mechanical agitation
1500mL ethyl acetate, there is white solid precipitation, filter and be dried in vacuo and to obtain white solid 585g, yield：89.2%.1H
NMR(400MHz,DMSO-d6) δ 7.98-7.56 (m, 5H), 7.50-7.29 (m, 4H), 7.14 (m, 2H), 4.86 (dd, J=
18.2,5.3Hz,1H),4.58–4.13(m,4H),4.13–3.94(m,2H),3.56–3.36(m,2H),2.31–1.76(m,
4H), 1.00 (dd, J=14.9,6.3Hz, 3H) .HRMS (ESI-TOF+)m/z Calcd.for C24H27N3O5 +[M+H]+:
438.4960,found 438.2026。
The preparation of the intermediate III of example 3
Intermediate II (1mol, 437g), n-octyl mercaptan 435mL and tert-butylamine 3L, room temperature are sequentially added into 10L single port bottles
Mechanic whirl-nett reaction 30 minutes.After completion of the reaction, 6 ethyl acetate are added into reactant mixture under conditions of mechanical agitation,
Filter and be dried in vacuo to obtain white solid, yield：95.8%, HPLC purity are 98.7%.1H NMR(400MHz,D2O)δ
4.24-4.06 (m, 2H), 3.80-3.66 (m, 1H), 2.97-2.73 (m, 2H), 2.07 (s, 1H), 1.68 (d, J=3.2Hz,
2H), 1.10 (dd, J=6.2,2.5Hz, 3H) .HRMS (ESI-TOF+)m/z Calcd.for C9H17N3O3 +[M+H]+:
216.1270,found 216.1342。
The preparation of the intermediate V of example 4
The N-Fmoc-O- tert-butyl groups-L-threonine (1mol, 397g), nitrogen stream condition are added to 5L four-hole boiling flask
Lower addition 1L anhydrous tetrahydro furans, mechanical agitation are allowed to dissolve and add 68g imidazoles, allow reaction bulb to be in low-temp reaction device,
Pivaloyl chloride is slowly added dropwise and maintenance reaction liquid temperature degree is less than -15 DEG C, it is separately that L-PROLINE benzyl ester hydrochloride and 68g imidazoles is molten
In 2L dichloromethane, obtained solution is slowly dropped in four-hole boiling flask and maintenance reaction liquid temperature degree is less than -15 DEG C, is dripped
Bi Hourang reaction solutions gradually return to room temperature.Suction filtration is carried out to reactant mixture and removes part accessory substance, filtrate rotary evaporator
Remove solvent and obtain light yellow oil, dissolve grease with ethyl acetate and be transferred in 5L separatory funnel, use successively
Watery hydrochloric acid and saturated sodium bicarbonate washing organic phase, ethyl acetate layer anhydrous magnesium sulfate is dry, filter, removes solvent under reduced pressure obtains
To crude product, in yellow oil, it is directly used in and reacts in next step.
Gained crude product is dissolved in absolute ethyl alcohol, is transferred in 3L four-hole boiling flask, and adds palladium carbon, the bar of nitrogen stream
Triethyl silicane is slowly added dropwise under part and is less than 10 DEG C using the temperature of ice-water bath maintenance reaction liquid, continues to react after being added dropwise
About 2 hours.Suction filtration removes palladium carbon, and filtrate decompression is evaporated off solvent and obtains light yellow oil, dissolves grease simultaneously with ethyl acetate
It is transferred in 5L separatory funnel, is extracted (4X 1L) using saturated sodium bicarbonate aqueous solution, is added excessively after merging aqueous phase
Watery hydrochloric acid is allowed to be acidified, then is extracted with ethyl acetate, and obtained ethyl acetate layer is dried with anhydrous magnesium sulfate, is filtered
And removing solvent under reduced pressure, gained grease adds n-hexane after being dissolved by heating with absolute ethyl alcohol, is allowed to be slowly cooled to room temperature
And be stirred continuously, it is to be crystallized filter and be dried in vacuo completely can obtain white solid 330g, yield：67%, HPLC purity is
98.5%.1H NMR(400MHz,CDCl3) δ 7.79 (d, J=7.5Hz, 2H), 7.62 (d, J=7.4Hz, 2H), 7.43 (t, J=
7.2Hz, 2H), 7.33 (dd, J=15.3,7.8Hz, 2H), 5.70 (d, J=7.8Hz, 1H), 4.68 (d, J=7.1Hz, 1H),
4.56-4.47 (m, 1H), 4.40 (t, J=10.0Hz, 2H), 4.24 (t, J=6.7Hz, 1H), 3.97 (dd, J=16.3,
10.5Hz,2H),3.80–3.66(m,1H),2.48–1.77(m,5H),1.33–1.02(m,12H).HRMS(ESI-TOF+)m/z
Calcd.for C28H34N2O6 +[M+H]+:495.2417,found 495.2497。
The preparation of the intermediate VII of example 5
Intermediate V (0.5mol, 247g) is added into 1L four-hole boiling flasks, 500mL mechanical agitations are added under the conditions of nitrogen stream
It is allowed to dissolve and add N-methylmorpholine, reaction bulb, which is placed in low-temp reaction device, makes reaction solution be cooled to -15 DEG C, is slowly added dropwise
Simultaneously maintenance reaction liquid temperature degree is less than -15 DEG C to pivaloyl chloride, and intermediate III is added into reaction bulb in solid form after being added dropwise
In, N-methylmorpholine is then slowly added dropwise, reaction solution is gradually returned to room temperature after being added dropwise.Reaction solution is transferred to 5L beakers
In, purified water (about 5 times of volumes) is added, is extracted with ethyl acetate, organic phase is washed and is dried with anhydrous magnesium sulfate, taken out
Filter, remove solvent under reduced pressure and obtain crude product, in yellow oil, be directly used in and react in next step.
Gained crude product is dissolved in ethyl acetate, and adds zinc bromide, and reaction 12h is stirred at room temperature.Added after reaction completely pure
Change water and stir 1 hour, stand and slowly separate out white solid, white solid 228g, yield can be obtained by filtering and being dried in vacuo：
72%.1H NMR(400MHz,DMSO-d6) δ 7.90 (d, J=7.5Hz, 2H), 7.75 (d, J=7.5Hz, 2H), 7.38 (m,
6H), 7.09 (d, J=19.0Hz, 2H), 4.68 (m, 3H), 4.46-3.94 (m, 7H), 3.90-3.51 (m, 5H), 2.22-1.63
(m,8H),1.21–0.92(m,6H).HRMS(ESI-TOF+)m/z Calcd.for C33H41N5O8 +[M+H]+:636.3955,
found636.3024。
The GLYX-13 of example 6 preparation
Embodiment 6.1
Intermediate VII (31.8g, 0.05mol) is dissolved in dichloromethane, and sequentially adds n-octyl mercaptan and tert-butylamine,
Room temperature mechanical stirring reaction 30 minutes.After completion of the reaction, acetic acid second is added into reactant mixture under conditions of mechanical agitation
Ester, filter and be dried in vacuo to obtain white solid 20g, yield：97%, HPLC purity are 99.8%.1H NMR(400MHz,D2O)
δ 4.60 (dd, J=17.6,7.7Hz, 1H), 4.41 (dd, J=15.4,9.8Hz, 1H), 4.25-4.08 (m, 2H), 3.86-
3.35(m,6H),2.37–2.14(m,2H),2.07–1.70(m,6H),1.20–0.99(m,6H).HRMS(ESI-TOF+)m/z
Calcd.for C18H31N5O6[M+H]+:414.2274,found 414.2121。
Embodiment 6.2
Intermediate VII (31.8g, 0.05mol) is dissolved in DMF, and sequentially adds n-octyl mercaptan and tert-butylamine, room temperature
Mechanic whirl-nett reaction 20 minutes.After completion of the reaction, ethyl acetate is added into reactant mixture under conditions of mechanical agitation, taken out
Filter and be dried in vacuo to obtain white solid 20g, yield：97%, HPLC purity are 99.7%.1H NMR(400MHz,D2O)δ4.60
(dd, J=17.6,7.7Hz, 1H), 4.41 (dd, J=15.4,9.8Hz, 1H), 4.25-4.08 (m, 2H), 3.86-3.35 (m,
6H),2.37–2.14(m,2H),2.07–1.70(m,6H),1.20–0.99(m,6H).HRMS(ESI-TOF+)m/z
Calcd.for C18H31N5O6[M+H]+:414.2274,found 414.2121。
Embodiment 6.3
Intermediate VII (31.8g, 0.05mol) is dissolved in ethanol, and sequentially adds n-octyl mercaptan and tert-butylamine, room temperature
Mechanic whirl-nett reaction 20 minutes.After completion of the reaction, ethyl acetate is added into reactant mixture under conditions of mechanical agitation, taken out
Filter and be dried in vacuo to obtain white solid 19.93g, yield：96.5%, HPLC purity are 99.8%.1H NMR(400MHz,D2O)
δ 4.60 (dd, J=17.6,7.7Hz, 1H), 4.41 (dd, J=15.4,9.8Hz, 1H), 4.25-4.08 (m, 2H), 3.86-
3.35(m,6H),2.37–2.14(m,2H),2.07–1.70(m,6H),1.20–0.99(m,6H).HRMS(ESI-TOF+)m/z
Calcd.for C18H31N5O6[M+H]+:414.2274,found 414.2121。
Claims (10)
1. a kind of GLYX-13 preparation method, it is characterised in that in organic solvent, deprotection tries described Formula VII compound
Under agent effect, Fmoc protection groups are removed, prepare GLYX-13, reaction equation is as follows：
2. preparation method according to claim 1, it is characterised in that described deprotecting regent is TBA and n-octyl mercaptan；
One or more of the organic solvent in methanol, ethanol, dichloromethane, DMSO, DMF, preferably dichloromethane.
3. preparation method according to claim 1, it is characterised in that the preparation method of described Formula VII compound includes：
Step 1) is in aprotic polar organic solvent, in the presence of condensing agent, alkali, formula III and Formula V reaction formula VI chemical combination
Thing；
Step 2) Formula IV compound further in organic solvent, under deprotecting regent effect, removes tert. butyl protection group；
Formula VII compound reaction equations are as follows：
4. preparation method according to claim 3, it is characterised in that the aprotic described in described step 1) is organic
One or more of the solvent in acetonitrile, tetrahydrofuran, dichloromethane, DMF, preferably DMF；Described condensing agent is selected from
One or more in EDCI, paratoluensulfonyl chloride, Cyanuric Chloride, pivaloyl chloride, condensing agent are preferably pivaloyl chloride；Described
One or more of the alkali in N-methylmorpholine, triethylamine, N- methylimidazoles, DIPEA, imidazoles, it is described
Alkali is preferably imidazoles；Deprotecting regent in described step 2) is selected from 85% phosphate aqueous solution, sodium iodide/cerous chloride and bromine
Change the one or more in zinc, preferably zinc bromide；Described solvent is dichloromethane, methanol, ethyl acetate, acetic acid first
One or more in ester, Ethyl formate, preferably ethyl acetate.
5. preparation method according to claim 3, it is characterised in that Formula II compound is in deprotecting regent and organic solvent
Under conditions of room temperature removing Fmoc protection groups, prepare compound of Formula III, reaction equation is as follows：
6. preparation method according to claim 5, it is characterised in that described deprotecting regent is diethylamine, tri-chlorination
Aluminium, dimethyl sulfoxide (DMSO) (DMSO) and the tert-butyl alcohol (TBA)/n-octyl mercaptan etc., preferably TBA/ n-octyl mercaptans；The solvent is first
Alcohol, ethanol, toluene and TBA, preferably TBA.
7. the preparation method of Formula IV compound according to claim 3, it is characterised in that described Formula V compound includes
Following reactions steps：
Step 1), the Fmoc-O- tert-butyl groups-L-threonine and proline benzyl ester hydrochloride in organic solvent, in condensing agent, alkali alkali
Intermediate IV is generated under the conditions of existing；
Step 2), intermediate IV make catalyst using palladium carbon in organic solvent, triethyl silicane removes as hydrogen donor high selectivity
Benzyl ester protection group formula V compounds；
Reaction equation is as follows：
8. preparation method according to claim 7, it is characterised in that condensation reagent in described step 1) is EDCI,
Paratoluensulfonyl chloride, Cyanuric Chloride and pivaloyl chloride, preferably pivaloyl chloride；The alkali is N-methylmorpholine, triethylamine, N- first
Base imidazoles, DIPEA and imidazoles, preferably imidazoles；The organic solvent is tetrahydrofuran, acetonitrile, N, N- dimethyl
Formamide (DMF) and dichloromethane etc., the preferably mixed solvent of tetrahydrofuran and dichloromethane；Hydrogen in described step 2)
Donor is formic acid, ammonium formate, hydrogen and triethyl silicane, preferably triethyl silicane；The organic solvent is selected from methanol, second
One or more in alcohol, tetrahydrofuran, ethyl acetate；Preferably ethanol.
9. preparation method according to claim 5, it is characterised in that former by starting of N- benzyloxycarbonyl groups-L- threonyls amine
Material, Cbz protection groups are sloughed by catalytic hydrogenation, and formula II compounds, including following reaction step are condensed with Fmoc-L- proline
Suddenly：
Step 1), N- benzyloxycarbonyl group-L- threonyls amine hydrogenate deprotection base benzyloxycarbonyl group under palladium carbon catalytic condition；
Step 2), Fmoc-L- proline and compound of formula I are in organic solvent using isobutyl chlorocarbonate as condensing agent production II
Compound；One or more of the solvent in tetrahydrofuran, acetonitrile, dichloromethane or DMF, preferred solvent DMF；
Described Formula II compound is prepared by following reaction：
10. formula III compound, Formula IV, compound, Formula VII compound：
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276414A (en) * | 2018-01-26 | 2018-07-13 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of citric acid tropsch imatinib |
| WO2018210336A1 (en) * | 2017-05-18 | 2018-11-22 | 江苏恩华药业股份有限公司 | Glyx-13 preparation method and intermediate component thereof |
| CN108864252A (en) * | 2018-07-24 | 2018-11-23 | 中国人民解放军军事科学院军事医学研究院 | The method for preparing NRX-1074 |
| WO2020047994A1 (en) * | 2018-09-06 | 2020-03-12 | 深圳翰宇药业股份有限公司 | Solid-phase synthesis method of abaloparatide |
| CN117843727A (en) * | 2024-03-07 | 2024-04-09 | 内蒙古大学 | Preparation method, intermediate and application of cyclopeptide toxin alpha-Amanitin and/or amanamide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098650A (en) * | 2013-04-15 | 2014-10-15 | 中国医学科学院药物研究所 | Synthesis and application of intermediate of atosiban |
| CN104109189A (en) * | 2013-04-18 | 2014-10-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Liquid-phase synthetic method of Thr-Pro-Pro-Thr tetrapiptide |
| WO2016014982A1 (en) * | 2014-07-24 | 2016-01-28 | Naurex, Inc. | N-methyl-d-aspartate receptor modulators and methods of making and using same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101692275B1 (en) * | 2010-02-11 | 2017-01-04 | 노오쓰웨스턴 유니버시티 | Secondary structure stabilized nmda receptor modulators and uses thereof |
| CN107474107B (en) * | 2017-05-18 | 2023-01-17 | 江苏恩华药业股份有限公司 | Process for the preparation of GLYX-13 and compounds useful for the preparation of GLYX-13 |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098650A (en) * | 2013-04-15 | 2014-10-15 | 中国医学科学院药物研究所 | Synthesis and application of intermediate of atosiban |
| CN104109189A (en) * | 2013-04-18 | 2014-10-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Liquid-phase synthetic method of Thr-Pro-Pro-Thr tetrapiptide |
| WO2016014982A1 (en) * | 2014-07-24 | 2016-01-28 | Naurex, Inc. | N-methyl-d-aspartate receptor modulators and methods of making and using same |
Non-Patent Citations (2)
| Title |
|---|
| JOSEPH R MOSKAL 等: "The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant", 《CURRENT NEUROPHARMACOLOGY》 * |
| 司天梅 等: "目前研究和开发更有效的抗抑郁药过程中存在的问题", 《上海精神医学》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018210336A1 (en) * | 2017-05-18 | 2018-11-22 | 江苏恩华药业股份有限公司 | Glyx-13 preparation method and intermediate component thereof |
| CN108276414A (en) * | 2018-01-26 | 2018-07-13 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of citric acid tropsch imatinib |
| CN108276414B (en) * | 2018-01-26 | 2019-07-23 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of citric acid tropsch imatinib |
| CN108864252A (en) * | 2018-07-24 | 2018-11-23 | 中国人民解放军军事科学院军事医学研究院 | The method for preparing NRX-1074 |
| CN108864252B (en) * | 2018-07-24 | 2020-07-28 | 中国人民解放军军事科学院军事医学研究院 | Method for preparing NRX-1074 |
| WO2020047994A1 (en) * | 2018-09-06 | 2020-03-12 | 深圳翰宇药业股份有限公司 | Solid-phase synthesis method of abaloparatide |
| CN117843727A (en) * | 2024-03-07 | 2024-04-09 | 内蒙古大学 | Preparation method, intermediate and application of cyclopeptide toxin alpha-Amanitin and/or amanamide |
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