CN102757478A - Allyl cysteinyl amino acid derivative and synthesis method and application thereof - Google Patents

Allyl cysteinyl amino acid derivative and synthesis method and application thereof Download PDF

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CN102757478A
CN102757478A CN2011101069320A CN201110106932A CN102757478A CN 102757478 A CN102757478 A CN 102757478A CN 2011101069320 A CN2011101069320 A CN 2011101069320A CN 201110106932 A CN201110106932 A CN 201110106932A CN 102757478 A CN102757478 A CN 102757478A
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sac
ome
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amino acid
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CN102757478B (en
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赵明
彭师奇
丁怡
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Capital Medical University
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Abstract

The invention discloses an allyl cysteinyl amino acid derivative and a synthesis method and application thereof. The synthesis method comprises the following steps: taking the most important active component allyl cysteine in garlic as a parent nucleus; performing amino acid modification on the parent nucleus to obtain the allyl cysteinyl amino acid derivative shown as a formula I, wherein pharmacokinetic properties of the parent nucleus are improved through structural modification, so as to improve the biological activity of the parent nucleus. Pharmacological and pharmacodynamic experiments show that the allyl cysteinyl amino acid derivative has excellent anti-inflammatory or analgesic activity and can be prepared into anti-inflammatory or analgesic medicines.

Description

Allyl cysteine amino acid derivative and compound method thereof and application
Technical field
The present invention relates to oligopeptides; Relate in particular to allyl cysteine amino acid derivative and compound method thereof with anti-inflammatory and analgesic activities; The invention further relates to their application in preparation anti-inflammatory or analgesic, belong to allyl cysteine amino acid derivative field.
Background technology
Inflammation is the major incentive of many major diseases (for example cancer, cardiovascular disorder and presenile dementia etc.).Preventing inflammation is the early stage step and the committed step of the said major disease of prevention, and seeking outstanding anti-inflammatory drug is one of focus of new drug research.
The history in existing several thousand of garlic food and medicament dual-purpose effect has pharmacologically actives such as enhance immunity function, anti-inflammatory, antibiotic, hypotensive, reducing blood-fat in recent years along with the deep discovery garlicin of garlic pharmacology activity research.Wherein the anti-inflammatory action of garlic causes international concern gradually.Garlic all has obvious suppression or killing action to diplococcus of various pathogens such as staphylococcus, meningitis, pneumonia etc., can treat inflammatory diseasess such as lobar pneumonia, pulmonary tuberculosis, wound suppuration, trachoma.The principle of garlicin antimicrobial antiphlogistic is owing to the sulphur atom of sulfocompound in the garlic is bred growth and the breeding that the sulphur atom in the necessary halfcystine molecule combines and suppressed bacterium with bacterial growth.2009, Yung-Hyun Cho found that garlic can reduce bacterial growth when the treatment chronic bacterial prostatitis, the amelioration of inflammation reaction, and when using, can work in coordination with effectiveness with its generation with CIPROFLOXACIN USP 24, reach better antiphlogistic effects.
Summary of the invention
One of the object of the invention provides one type of allyl cysteine amino acid derivative with anti-inflammatory and antalgic activity;
Two of the object of the invention provides a kind of method of synthetic above-mentioned allyl cysteine amino acid derivative;
Three of the object of the invention is that said allyl cysteine amino acid derivative is prepared into anti-inflammatory or analgesic medicine.
Above-mentioned purpose of the present invention realizes through following technical scheme:
Allyl cysteine amino acid derivative with anti-inflammatory and antalgic activity, its structural formula are shown in the formula I:
Figure BDA0000057748460000011
formula I
Wherein, R is selected from hydrogen, CH 3, CH (CH 3) 2, CH (CH 3) CH 2CH 3, CH 2CH (CH 3) 2, CH 2C 6H 4-OH-p, CH (OH) CH 3, Indole-5-yl-CH 2, CH 2CH 2CO 2CH 3, CH 2OH, CH 2CH 2CH 2CH 2NHCOCH (NH 2) CH 2SCH 2CHCH 2, CH 2CO 2CH 3, Imidazole-4-yl-CH 2, CH 2CH 2SCH 3Or CH 2C 6H 5
Two of the object of the invention provides a kind of method of synthetic above-mentioned allyl cysteine amino acid derivative, and this method comprises:
1) reaction of L-halfcystine and 3-bromopropylene obtains allyl cysteine (SAC);
2) allyl cysteine (SAC) with (BOC) 2Reaction obtains Boc-SAC;
3) reaction of amino acid and methyl alcohol obtains HClAA-OMe;
4) Boc-SAC and HClAA-OMe condensation obtain Boc-SAC-AA-OMe;
5) Boc-SAC-AA-OMe sloughs formicester and generates Boc-SAC-AA;
6) Boc-SAC-AA is removed Boc, promptly get.
Wherein, preferred, in the step 1) L-halfcystine is reacted three hours formation allyl cysteines (SAC) with the 3-bromopropylene down at 0 ℃ in ammoniacal liquor;
Step 2) in preferred in containing the dioxane of alkalescent water SAC (allyl cysteine) with (BOC) 2Reaction gets Boc-SAC;
Preferred under the effect of sulfur oxychloride in the step 3), amino acid and methyl alcohol reaction obtain HClAA-OMe; Wherein, described amino acid is selected from Gly, Ala, Val, Ile, Leu, Tyr, Thr, Pro, Glu, Ser, Lys, Asp, Trp, Met or Phe;
Preferably in the presence of DCC and HOBt, Boc-SAC is condensed into Boc-SAC-AA-OMe with HClAA-OMe in anhydrous THF in the step 4);
Preferred in containing the basic soln of NaOH in the step 5), Boc-SAC-AA-OMe sloughs formicester and generates Boc-SAC-AA;
In the step 6) preferred in containing the ETHYLE ACETATE of hydrogenchloride Boc-SAC-AA remove Boc and generate SAC-AA.
The present invention utilizes that most important activeconstituents allyl cysteine is parent nucleus in the garlic; Carry out amino acid modified to it; Obtain the allyl cysteine amino acid derivative shown in the formula I, through its structural modification is improved its medicine for character, and then improve the biological activity of parent nucleus.The pharmacology pharmacodynamic experiment shows that allyl cysteine amino acid derivative of the present invention has excellent anti-inflammatory or analgesic activities, can it be prepared into anti-inflammatory or analgesic.
The present invention also provides a kind of anti-inflammatory or analgesic pharmaceutical composition, and this pharmaceutical composition is formed by treating compound and the pharmaceutically acceptable carrier shown in the formula I that goes up significant quantity.Said carrier includes but not limited to: glucose, salt solution, glycerine, ethanol, zero(ppm) water etc.; Described pharmaceutical composition can be prepared into injection or oral prepns according to the drug formulation process of routine.The aqueous solution that for example, can use saline water or contain glucose is prepared into injection formulations as carrier with it; Or it is prepared into oral prepns according to the oral prepns method of routine, for example: various oral prepns such as enteric coated capsule, colon site-specific drug.
The dosage of pharmaceutical composition of the present invention is the significant quantity in the treatment, and concrete dosage should be with reference to factors such as route of administration and patient health situations, as a reference: every day about 3-120 microgram/Kg body weight, be preferably 35 micrograms/Kg body weight.
Description of drawings
The structural formula of Fig. 1 allyl cysteine amino acid derivative of the present invention.
Fig. 2 allyl cysteine synthetic route of the present invention synoptic diagram: i) 3-bromopropylene and ammoniacal liquor; Ii) (Boc) 2O and 2N NaOH; Iii) DCC, HOBt, NMM and amino acid methyl ester; Iv) 4N NaOH; V) hydrogenchloride ethyl acetate solution (4N); R is selected from hydrogen, CH 3, CH (CH 3) 2, CH (CH 3) CH 2CH 3, CH 2CH (CH 3) 2, CH 2C 6H 4-OH-p, CH (OH) CH 3, Indole-5-yl-CH 2, CH 2CH 2CO 2CH 3, CH 2OH, CH 2CH 2CH 2CH2NHCOCH (NH 2) CH 2SCH 2CHCH 2, CH 2CO 2CH 3, Imidazole-4-yl-CH 2, CH 2CH 2SCH 3Or CH 2C 6H 5
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
Embodiment 1 preparation allyl cysteine (SAC)
Add 9g (74.3mmol) L-halfcystine in the reaction flask, use the NH of 200ml concentration as 2M 4After the OH dissolving, add 14g (115.7mmol) 3-bromopropylene, reflect 3h down at 0 ℃.Be concentrated into driedly, obtain colorless solid.Water-ethyl alcohol recrystallization obtains title compound.ESI-MS(m/e)：162[M+H] +. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝5.85-5.65(m，1H)，5.05-5.20(m，2H)，3.75-3.85(m，1H)，3.05-3.18(d，J＝7.2Hz，2H)，2.80-3.05(m，2H).
Embodiment 2 preparation Boc-SAC
Take by weighing 640mg SAC in reaction flask, add the 8ml water dissolution, under the condition of ice bath, slowly drip 1N NaOH 4ml, will be dissolved with 1.040mg (Boc) 2The dioxane of O is slowly poured into wherein, and transferring reaction solution pH is 9, reaction 72h, during whenever take out CO in the reaction system with single-pass at a distance from 3h 2Once.The TLC detection reaction fully after, transferring reaction solution pH is 7, revolves except that dioxane, transferring reaction solution pH again is 2, with ethyl acetate extraction reaction solution three times, the ethyl acetate layer that obtains comes together with saturated NaCl and gives a baby a bath on the third day after its birth inferiorly, obtains ethyl acetate layer and uses anhydrous Na SO 4Dried overnight removes by filter NaSO 4, revolve dry ethyl acetate and obtain title compound.ESI-MS(m/e)：282[M+H] +.
Embodiment 3 preparation HClGly-OMe (1a)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Gly is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：89[M+H] +
Embodiment 4 preparation HClAla-OMe (1b)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Ala is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：104[M+H] +
Embodiment 5 preparation HClVal-OMe (1c)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Val is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：132[M+H] +
Embodiment 6 preparation HCl HClIle-OMe (1d)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Ile is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：146[M+H] +
Embodiment 7 preparation HCl HClLeu-OMe (1e)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Leu is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：146[M+H] +
Embodiment 8 preparation HClTyr-OMe (1f)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Tyr is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：196[M+H] +
Embodiment 9 preparation HClThr-OMe (1g)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Thr is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：134[M+H] +
Embodiment 10 preparation HClPro-OMe (1h)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Pro is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：130[M+H] +
Embodiment 11 preparation HClGlu-OMe 2(1i)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Glu is added in the reaction system, reaction 36h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：176[M+H] +
Embodiment 12 preparation HClSer-OMe (1j)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Ser is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：120[M+H] +
Embodiment 13 preparation HClLys-OMe (1k)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Lys is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：161[M+H] +
Embodiment 14 preparation HClAsp-OMe 2(1l)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Asp is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：162[M+H] +
Embodiment 15 preparation HClTrp-OMe (1m)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Trp is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：219[M+H] +
Embodiment 16 preparation HClMet-OMe (1n)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Met is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：164[M+H] +
Embodiment 17 preparation HClPhe-OMe (1o)
Measure 30ml methyl alcohol, under condition of ice bath, slowly drip 2.6ml SOCl 2, activation 30min.10mmol L-Phe is added in the reaction system, reaction 24h, the TLC detection reaction is complete, with single-pass reaction solution is drained, and add small amount of methanol and drain, 3 times repeatedly, add a small amount of ether again and drain, three times repeatedly, obtain title compound.ESI-MS(m/e)：180[M+H] +
Embodiment 18 preparation Boc-SAC-Gly-OMe (2a)
Take by weighing 2.61g Boc-SAC in reaction flask; With a small amount of anhydrous THF dissolving; Add 1-hydroxy benzo triazole (HoBt) 1.45g under the condition of ice bath; Add N behind the 5min again, N '-NSC 57182 (DCC) will be dissolved with 10mmol HClGly-OMe and pH and be adjusted to 9 anhydrous THF with NMM and pour in the reaction system behind the 20min.After reaction 12h, TLC detected demonstration reflection fully, with reacting liquid filtering, filtrating was used acetic acid ethyl dissolution after revolving and doing, and uses 5%NaHCO successively 3Solution, saturated NaCl solution, 5%KHSO 4Solution, saturated NaCl solution, saturated NaHCO 3Solution, saturated NaCl solution collection is given a baby a bath on the third day after its birth inferior, and the ethyl acetate layer that obtains is used anhydrous Na SO 4Dried overnight.Remove by filter NaSO 4, filtrating is revolved the dried title compound that obtains.ESI-MS(m/e)：355[M+Na] +.Mp：48℃ (c＝0.51，CH 3OH).IR(KBr)：3313.71，3003.17，2972.31，1761.01，1101.35，985.62，925.83，705.95. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.45-8.25(t，J＝5.4Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)5.85-5.65(m，1H)，5.05-5.20(m，2H)，4.10-4.00(m，1H)，3.95-3.75(m，2H)，3.70-3.55(s，3H)，3.25-3.05(d，J＝6.9Hz，1H)，2.95-2.50(m，2H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝171.67，170.53，155.74，134.87，117.66，78.71，55.58，54.17，28.65，25.79，24.92.
Embodiment 19 preparation Boc-SAC-Ala-OMe (2b)
According to the method for embodiment 18, Boc-SAC and HClAla-OMe reaction obtain title compound.ESI-MS(m/e)：369[M+Na] +.Mp：64℃.
Figure BDA0000057748460000072
(c＝0.53，CH 3OH).IR(KBr)：3446.79，3319.49，3082.25，1749.44，1543.05，1166.93，1049.28，678.94. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.45-8.25(d，J＝7.2Hz，1H)，7.00-6.85(d，J＝8.1Hz，1H)，5.85-5.65(m，1H)，5.05-5.20(m，2H)，4.40-4.20(m，1H)，4.10-4.00(m，1H)，3.95-3.75(m，2H)，3.60(s，3H)，3.35-3.15(d，J＝4.5Hz，2H)，2.85-2.65(m，1H)，2.60-2.45(m，2H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝173.24，171.06，155.71，134.91，117.64，78.66，54.22，52.33，48.03，34.40，33.12，28.63，17.38.Elem.
Embodiment 20 preparation Boc-SAC-Val-OMe (2c)
According to the method for embodiment 18, Boc-SAC and HClVal-OMe reaction obtain title compound.ESI-MS(m/e)：397[M+Na] +.Mp：114℃.
Figure BDA0000057748460000081
(c＝0.51，CH 3OH).IR(KBr)：3323.35，2970.38，1751.36，1681.93，1649.14，1535.34，1290.38，1056.99，1022.27. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.15-8.05(d，J＝8.4Hz，1H)，7.05-6.95(d，J＝8.7Hz，1H)5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.30-4.10(m，2H)，3.70-3.55(s，3H)，3.25-3.05(d，J＝8.1Hz，2H)，2.95-2.50(m，3H)，2.15-1.95(m，1H)，1.40(s，9H)，1.00-0.75(t，J＝6.0Hz，5H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.17，171.48，155.68，134.88，117.64，78.70，57.71，54.36，52.18，34.35，32.79，30.52，28.60，19.31，18.53.Elem.
Embodiment 21 preparation Boc-SAC-Ile-OMe (2d)
According to the method for embodiment 18, Boc-SAC and HClIle-OMe reaction obtain title compound.ESI-MS(m/e)：411[M+Na] +.Mp：93℃.
Figure BDA0000057748460000082
(c＝0.49，CH 3OH).IR(KBr)：3321.42，1747.51，1649.14，1556.55，1286.52，1172.72，927.76. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.15-8.00(d，J＝8.1Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.30-4.10(m，2H)，3.70-3.55(s，3H)，3.25-3.05(d，J＝6.9Hz，2H)，2.80-2.65(m，1H)，2.15-1.95(m，3H)，1.90-1.70(m，1H)，1.40(s，9H)，1.00-0.75(m，5H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.13，171.33，155.66，134.92，128.82，128.26，117.58，78.76，56.72，54.39，52.10，36.89，34.43，31.03，15.77，11.50.Elem.
Embodiment 22 preparation Boc-SAC-Leu-OMe (2e)
According to the method for embodiment 18, Boc-SAC and HClLeu-OMe reaction obtain title compound.ESI-MS(m/e)：411[M+Na] +.Mp：98℃. (c＝0.51，CH 3OH).IR(KBr)：3338.78，2980.02，1759.08，1683.86，2525.69，1367.53，1249.87，1155.36. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.15-8.00(d，J＝8.1Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.20(m，1H)，4.20-4.05(m，1H)，3.70-3.55(s，3H)，3.25-3.05(d，J＝8.2Hz，2H)，2.80-2.65(m，1H)，2.15-1.95(m，3H)，1.90-1.70(m，1H)，1.40(s，9H)，1.00-0.75(m，5H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝173.12，171.26，155.63，134.87，117.63，78.68，54.35，52.29，50.64，34.38，32.83，28.59，24.51，23.25，21.69.
Embodiment 23 preparation Boc-SAC-Tyr-OMe (2f)
According to the method for embodiment 18, Boc-SAC and HClTyr-OMe reaction obtain title compound.ESI-MS(m/e)：461[M+Na] +.
Figure BDA0000057748460000091
(c＝0.49，CH 3OH).IR(KBr)：3475.73，1753.29，1726.29，1446.61，1367.53，1269.16，1051.20，840.96. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.30-8.10(d，J＝7.5Hz，1H)，7.15-6.95(m，3H)，6.75-6.50(d，J＝8.4Hz，2H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.20(m，1H)，4.20-4.05(m，1H)，3.70-3.55(s，3H)，3.50-3.25(m，2H)，3.25-3.05(d，J＝8.2Hz，2H)，2.80-2.65(m，2H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.16，171.12，156.65，155.62，134.83，130.45，127.15，117.65，115.54，78.74，54.26，52.24，36.39，34.36，33.07，28.62.
Embodiment 24 preparation Boc-SAC-Thr-OMe (2g)
According to the method for embodiment 18, Boc-SAC and HClThr-OMe reaction obtain title compound.ESI-MS(m/e)：376[M+Na] +.Mp：65℃.
Figure BDA0000057748460000092
(c＝0.51，CH 3OH).IR(KBr)：3485.37，2517.10，1720.50，1670.35，1575.84，1506.41，1282.66，1195.87，1136.07. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝7.90-7.75(d，J＝8.7Hz，1H)，7.20-7.05(d，J＝8.7Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.70-3.55(s，3H)，3.45(s，1H)，3.25-3.10(m，2H)，2.80-2.65(m，1H)，2.60-2.45(m，2H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝171.69，171.33，155.76，134.95，117.62，78.77，66.71，58.07，54.47，52.33，34.32，32.83，28.62，20.47.
Embodiment 25 preparation Boc-SAC-Pro-OMe (2h)
According to the method for embodiment 18, Boc-SAC and HClPro-OMe reaction obtain title compound.ESI-MS(m/e)：395[M+Na] +. (c＝0.52，CH 3OH).IR(KBr)：2980.02，1747.51，1733.86?1710.86，1647.21，1519.91，1488.11?1438.90，1365.60，1166.93，1045.42. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝7.20-7.05(d?J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，2H)，4.20-4.05(m，1H)，3.70-3.55(s，3H)，3.45(s，1H)，3.45-3.10(m，3H)，2.80-2.65(m，1H)，2.60-2.45(m，1H)，2.40-2.05(m，1H)，2.05-1.75(m，3)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.57，169.67，155.31，135.01，117.55，78.60，59.07，46.98，40.85，40.29，34.66，33.09，25.02.
Embodiment 26 preparation Boc-SAC-Glu-OMe (2i)
According to the method for embodiment 18, Boc-SAC and HClGlu-OMe reaction obtain title compound.ESI-MS(m/e)：441[M+Na] +.Mp：105℃
Figure BDA0000057748460000101
(c＝0.52，CH 3OH).IR(KBr)：3315.63，1749.44，1726.29，1656.85，1517.98，1436.97，1161.15，1112.93，920.05. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.40-8.20(d，J＝8.5Hz，1H)，7.05-6.90(d，J＝8.1Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.70-3.65(s，3H)，3.65-3.55(s，3H)，3.45(m，1H)，3.25-3.10(m，2H)，2.80-2.65(m，1H)，2.60-2.45(m，1H)，2.45-2.30(t，J＝7.5Hz，1H)，2.15-1.95(m，1H)，1.95-1.75(m，1H)，1.40(s，9H)，1.15-1.05(t，J＝7.5Hz，1H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝173.02，171.71，168.00，134.39，118.26，65.35，52.49，52.10，51.85，48.99，34.38，31.54，29.92，26.47，15.53.
Embodiment 27 preparation Boc-SAC-Ser-OMe (2j)
According to the method for embodiment 18, Boc-SAC and HClSer-OMe reaction obtain title compound.ESI-MS(m/e)：364[M+H] +.
Figure BDA0000057748460000102
(c＝0.52，CH 3OH).IR(KBr)：3599.64，2998.95，1651.57，1435.55，1431.12，1334.09，1128.73，1205.49，1005.26，994.66. 1HNMR(300MHz，DMSO-d 6)：δ/pp＝8.40-8.20(d，J＝7.5Hz，1H)，7.05-6.90(d，J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.75-3.25(m，1H)，3.70-3.65(s，3H)，3.45-3.30(m，1H)，3.25-3.10(d，J＝4.8Hz?3H)，2.80-2.65(m，1H)，2.60-2.45(m，1H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝171.37，171.24，155.53，134.92，117.62，78.71，63.33，61.63，55.62，55.06，54.24，53.24，52.34，49.05，39.08，33.14，28.61.
Embodiment 28 preparations 2 (Boc-SAC)-Lys-OMe (2k)
According to the method for embodiment 18, Boc-SAC and HClLys-OMe reaction obtain title compound.ESI-MS(m/e)：669[M+Na] +.
Figure BDA0000057748460000103
(c＝0.48，CH 3OH).IR(KBr)：3275.13，2931.80，1747.51，1639.49，1699.67，1533.41，1249.87，1172.72，1049.28，1022.27，920.77. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.40-8.20(d，J＝8.5Hz，1H)，7.95-7.85(t，J＝4.8Hz，1H)，6.95-6.90(d，J＝8.7Hz，1H)，6.95-6.80(d，J＝8.1Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.20-4.15(m，1H)，4.15-4.08(m，1H)，4.05-4.00(m，1H)，3.70-3.65(s，3H)，3.30(s，1H)，3.20-3.10(t，J＝8.2Hz，4H)，2.80-2.60(m，2H)，2.60-2.55(m，4H)，1.80-1.55(m，2H)，1.40(s，20H)，1.30-1.20(m，2H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.74，171.29，170.75，155.66，134.88，134.84，117.64，78.69，52.30，52.27，34.41，34.28，33.01，28.95，28.62，22.91.
Embodiment 29 preparation Boc-SAC-Asp-OMe 2(2l)
According to the method for embodiment 18, Boc-SAC and HClAsp-OMe 2Reaction obtains title compound.ESI-MS(m/e)：547[M+Na] +.Mp：107℃ (c＝0.52，CH 3OH).IR(KBr)：3354.21，2933.73，1795.08，1649.14，1521.84，1436.97，1367.53，1166.93，1056.99，929.69. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝7.45-7.55(d，J＝5.4Hz，1H)，6.65-6.55(d，J＝7.5Hz，1H)，6.15-6.00(d，J＝5.1Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，5.25-5.05(m，4H)，4.85-4.65(m，2H)，4.65-4.45(m，1H)，3.85-3.75(s，3H)，3.75-3.65(s，3H)，3.55-3.45(m，3H)，3.25-3.10(m，4H)，2.55-2.75(m，1H)，1.95-1.75(m，1H)，1.40(s，9H)，1.30-1.15(t，J＝6.9Hz，4H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝171.04，170.87，133.71，133.63，117.97，117.83，65.81，52.62，52.53，52.10，35.09，35.07，32.60，32.43，28.32，15.24.
Embodiment 30 preparation Boc-SAC-Trp-OMe (2m)
According to the method for embodiment 18, Boc-SAC and HClTrp-OMe reaction obtain title compound.ESI-MS(m/e)：464[M+H] +.Mp：115℃
Figure BDA0000057748460000112
(c＝0.52，CH 3OH).IR(KBr)：3311.78，2915.09，2835.36，1737.86，1361.74，1338.60，1249.87，1217.06，927.76 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝10.95-10.85(s，1H)，8.30-8.20(m，1H)，7.55-7.45(d，J＝7.5Hz，1H)，7.40-7.35(d，J＝8.1Hz，1H)，7.20-7.15(s，1H)，7.15-6.90(m，3H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.65-3.55(s，3H)，3.25-3.10(m，4H)，2.80-2.65(m，1H)，2.60-2.45(m，1H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/pp＝172.40，171.20，155.68，136.55，134.84，127.53，124.16，121.44，118.91，118.42，117.64，111.89，109.52，78.77，54.32，53.50，52.28，34.38，33.13，28.61，27.47.
Embodiment 31 preparation Boc-SAC-Met-OMe (2n)
According to the method for embodiment 18, Boc-SAC and HClMet-OMe reaction obtain title compound.ESI-MS(m/e)：407[M+H] +.Mp：65℃. (c＝0.53，CH 3OH).IR(KBr)：3547.09，3116.97，1907.60，1707.60，1761.01，1558.48，1521.84，1290.38，1274.95，775.68. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.30-8.20(d，J＝7.8Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.65(s，3H)，3.25-3.10(d，J＝7.2Hz，2H)，2.80-2.65(m，1H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.41，171.42，155.67，154.81，134.80，117.69，78.70，54.36，52.43，51.25，34.34，32.67，30.96，29.82，28.60，15.02.
Embodiment 32 preparation Boc-SAC-Phe-OMe (2o)
According to the method for embodiment 18, Boc-SAC and HClPhe-OMe reaction obtain title compound.ESI-MS(m/e)：445[M+Na] +.Mp：80℃
Figure BDA0000057748460000122
(c＝0.50，CH 3OH).IR(KBr)：3348.42，2980.02，2360.87，2339.65，1739.79，1656.85，1525.69，1392.61，1022.27，700.16. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.40-8.20(d，J＝7.5Hz，2H)，6.95-6.85(d，J＝8.4Hz，2H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.65(s，3H)，3.50-3.35(s，3H)，3.25-3.10(d，J＝7.2Hz，2H)，3.10-3.00(m，2H)，2.80-2.65(m，2H)，1.40(s，9H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.05，171.17，155.59，137.41，134.83，129.56，128.69，127.01，117.65，78.71，54.32，53.91，52.31，37.08，34.36，33.06，28.62.
Embodiment 33 preparation Boc-SAC-Gly (3a)
Take by weighing Boc-SAC-Gly-OMe 800mg in reaction flask, with a small amount of THF dissolving, the NaOH solution that slowly drips 2N under the ice bath is 13 until reaction solution pH, and reaction process keeps ice bath, reaction 2.5h.The TLC monitoring reaction is used saturated KHSO after finishing 4Conditioned reaction liquid pH is 7, revolves except that THF, and be 2 with the reaction solution pH regulator again, wash reaction solution three times with the ETHYLE ACETATE collection, the ethyl acetate layer that obtains spends the night with anhydrous sodium sulfate drying with saturated NaCl washing three times subsequently.Filtering sodium sulfate revolves except that ETHYLE ACETATE and promptly obtains title compound.
Embodiment 34 preparation Boc-SAC-Ala (3b)
Method according to embodiment 33 prepares title compound by Boc-SAC-Ala-OMe.
Embodiment 35 preparation Boc-SAC-Val (3c)
Method according to embodiment 33 prepares title compound by Boc-SAC-Val-OMe.
Embodiment 36 preparation Boc-SAC-Ile (3d)
Method according to embodiment 33 prepares title compound by Boc-SAC-Ile-OMe.
Embodiment 37 preparation Boc-SAC-Leu (3e)
Method according to embodiment 33 prepares title compound by Boc-SAC-Leu-OMe.
Embodiment 38 preparation Boc-SAC-Tyr (3f)
Method according to embodiment 33 prepares title compound by Boc-SAC-Tyr-OMe.
Embodiment 39 preparation Boc-SAC-Thr (3g)
Method according to embodiment 33 prepares title compound by Boc-SAC-Thr-OMe.
Embodiment 40 preparation Boc-SAC-Pro (3h)
Method according to embodiment 33 prepares title compound by Boc-SAC-Pro-OMe.
Embodiment 41 preparation Boc-SAC-Glu (3i)
According to the method for embodiment 33, by Boc-SAC-Glu-OMe 2Prepare title compound.
Embodiment 41 preparation Boc-SAC-Ser (3j)
Method according to embodiment 33 prepares title compound by Boc-SAC-Ser-OMe.
Embodiment 42 preparations 2 (Boc-SAC)-Lys (3k)
According to the method for embodiment 33, prepare title compound by 2 (Boc-SAC)-Lys-OMe.
Embodiment 43 preparation Boc-SAC-Asp (3l)
According to the method for embodiment 33, by Boc-SAC-Asp-OMe 2Prepare title compound.
Embodiment 44 preparation Boc-SAC-Trp (3m)
Method according to embodiment 33 prepares title compound by Boc-SAC-Trp-OMe.
Embodiment 45 preparation Boc-SAC-Met (3n)
Method according to embodiment 33 prepares title compound by Boc-SAC-Met-OMe.
Embodiment 46 preparation Boc-SAC-Phe (3o)
Method according to embodiment 33 prepares title compound by Boc-SAC-Phe-OMe.
Embodiment 46 preparation SAC-Gly (4a)
Take by weighing 600mg Boc-SAC-Gly in reaction flask,, under condition of ice bath, slowly drip 4N hydrochloric ethyl acetate 9ml, be reflected under the condition of drying, ice bath and continue 2h with the dissolving of a small amount of anhydrous ethyl acetate.The TLC monitoring reaction finishes, and reaction solution is drained with water pump, adds a small amount of dry ETHYLE ACETATE and drains repeatedly three times, adds a small amount of anhydrous diethyl ether again and drains, three times repeatedly.Promptly obtain title compound.ESI-MS(m/e)：219[M+H] +.Mp：89℃
Figure BDA0000057748460000141
(c＝0.49，CH 3OH).IR(KBr)：2935.66，1680.00，1579.70，1519.91，1398.39，1249.87，993.34，933..55. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.45-8.25(t，J＝5.4Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.05-5.20(m，2H)，4.10-4.00(m，1H)，3.95-3.75(m，2H)，3.25-3.05(d，J＝6.9Hz，1H)，2.95-2.50(m，2H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝170.07，168.37，134.47，51.99，41.14，34.38，31.62.
Embodiment 47 preparation SAC-Ala (4b)
Method according to embodiment 46 prepares title compound by Boc-SAC-Ala.ESI-MS(m/e)：233[M+H] +.Mp：127℃.
Figure BDA0000057748460000142
(c＝0.51，CH 3OH).IR(KBr)：2924.09，1735.93，1674.21，1562.34，1489.05，1213.23，1138.00，991.41，923.90. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.45-8.25(d，J＝7.2Hz，1H)，7.00-6.85(d，J＝8.1Hz，1H)，5.85-5.65(m，1H)，5.05-5.20(m，2H)，4.40-4.20(m，1H)，4.10-4.00(m，1H)，3.95-3.75(m，2H)，3.35-3.15(d，J＝4.5Hz，2H)，2.85-2.65(m，1H)，2.60-2.45(m，2H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝173.68，172.43，167.34，134.44，118.33，51.94，48.29，48.19，34.36，31.56，21.21，17.24.
Embodiment 48 preparation SAC-Val (4c)
Method according to embodiment 46 prepares title compound by Boc-SAC-Val.ESI-MS(m/e)：261[M+H] +.
Figure BDA0000057748460000143
(c＝0.51，CH 3OH).IR(KBr)：2488.17，1687.71，1541.12，1213.23，1143.79，989.48，921.97. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.15-8.05(d，J＝8.4Hz，1H)，7.05-6.95(d，J＝8.7Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.30-4.10(m，2H)，3.25-3.05(d，J＝8.1Hz，2H)，2.95-2.50(m，3H)，2.15-1.95(m，1H)，1.00-0.75(t，J＝6.0Hz，5H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.60，167.99，134.45，118.31，58.09，51.98，34.46，31.84，30.47，19.53，18.48.
Embodiment 49 preparation SAC-Ile (4d)
Method according to embodiment 46 prepares title compound by Boc-SAC-Ile.ESI-MS(m/e)：275[M+H] +.
Figure BDA0000057748460000151
(c＝0.48，CH 3OH).IR(KBr)：3271.27，2922.16，1654.92，1527.62，1367.53，1166.93，921.97. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.15-8.00(d，J＝8.1Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.30-4.10(m，2H)，3.25-3.05(d，J＝6.9Hz，2H)，2.80-2.65(m，1H)，2.15-1.95(m，3H)，1.90-1.70(m，1H)，1.00-0.75(m，5H). 13CNMR(75MHz，DMSO-d 6)：δ/ppm＝172.58，167.86，134.41，57.10，51.92，37.02，34.39，31.74，25.12，15.98，11.86.
Embodiment 50 preparation SAC-Leu (4e)
Method according to embodiment 46 prepares title compound by Boc-SAC-Leu.ESI-MS(m/e)：275[M+H] +.
Figure BDA0000057748460000152
(c＝0.49，CH 3OH).IR(KBr)：2922.16，1722.43，1672.28，1550.77，1471.69，1201.65，92.05. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.15-8.00(d，J＝8.1Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.30-4.10(m，2H)，3.25-3.05(d，J＝6.9Hz，2H)，2.80-2.65(m，1H)，2.15-1.95(m，3H)，1.90-1.70(m，1H)，1.00-0.75(m，5H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.58，167.86，134.41，57.10，51.92，37.02，34.39，31.74，25.12，15.98，11.86.
Embodiment 51 preparation SAC-Tyr (4f)
Method according to embodiment 46 prepares title compound by Boc-SAC-Tyr.ESI-MS(m/e)：325[M+H] +.
Figure BDA0000057748460000153
(c＝0.51，CH 3OH).IR(KBr)：2783.28，1722.43，1516.05，1228.66，1105.21，925.83，839.03，734.88，542.00. 1H?NMR(300MHz，DMSO-d 6)：δ/ppm＝8.30-8.10(d，J＝7.5Hz，1H)，7.15-6.95(m，3H)，6.75-6.50(d，J＝8.4Hz，2H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.20(m，1H)，4.20-4.05(m，1H)，3.50-3.25(m，2H)，3.25-3.05(d，J＝8.2Hz，2H)，2.80-2.65(m，2H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝171.65，167.90，156.68，134.48，130.54，127.05，118.32，115.64，65.38，54.83，52.40，51.09，36.28，34.43，15.64.
Embodiment 52 preparation SAC-Thr (4g)
Method according to embodiment 46 prepares title compound by Boc-SAC-Thr.ESI-MS(m/e)：263[M+H] +.
Figure BDA0000057748460000161
(c＝0.53，CH 3OH).IR(KBr)：3080.32，1681.93，2785.21，1942.32，1558.48，1463.97，1377.17，1207.44?1132.21，1055.06. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝7.90-7.75(d，J＝8.7Hz，1H)，7.20-7.05(d，J＝8.7Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.45(s，1H)，3.25-3.10(m，2H)，2.80-2.65(m，1H)，2.60-2.45(m，2H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.44，171.81，168.17，134.49，118.32，66.72，58.50，51.89，34.32，31.99，20.84.
Embodiment 53 preparation SAC-Pro (4h)
Method according to embodiment 46 prepares title compound by Boc-SAC-Pro.ESI-MS(m/e)：258[M+H] +.Mp：114.9-115.2℃
Figure BDA0000057748460000162
(c＝0.53，CH 3OH).IR(KBr)：2891.30，1616.35，1409.96，1369.46，1224.80，1190.08，991.41，918.12，738.74 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝7.20-7.05(d，J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，2H)，4.20-4.05(m，1H)，3.45(s，1H)，3.45-3.10(m，3H)，2.80-2.65(m，1H)，2.60-2.45(m，1H)，2.40-2.05(m，1H)，2.05-1.75(m，3H) 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.37，169.48，134.75，118.42，60.22，47.00，39.35，32.18，30.49，28.62，22.25.
Embodiment 54 preparation SAC-Glu (4i)
Method according to embodiment 46 prepares title compound by Boc-SAC-Glu.ESI-MS(m/e)：290[M+H] +.
Figure BDA0000057748460000163
(c＝0.49，CH 3OH).IR(KBr)：3300.20，2432.24，1737.86，1666.50，1558.48，1487.12，1408.04，1228.66，1116.78，991.41，921.97. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.40-8.20(d，J＝8.5Hz，1H)7.05-6.90(d，J＝8.1Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.45(m，1H)，3.25-3.10(m，2H)，2.80-2.65(m，1H)，2.60-2.45(m，1H)，2.45-2.30(t，J＝7.5Hz，1H)，2.15-1.95(m，1H)，1.95-1.75(m，1H)，1.15-1.05(t，J＝7.5Hz，1H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝1174.12，172.86，167.84，134.44，118.35，51.94，34.41，31.64，30.41，26.88，21.54.
Embodiment 55 preparation SAC-Ser (4j)
Method according to embodiment 46 prepares title compound by Boc-SAC-Ser.ESI-MS(m/e)：249[M+H] +.
Figure BDA0000057748460000171
(c＝0.50，CH 3OH).IR(KBr)：3194.12，1720.50，1672.28，1552.70，1490.97，1384.89，1205.51，1124.50，1047.35，991.41，927.76，738.74. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.40-8.20(d，J＝7.5Hz，1H)，7.05-6.90(d，J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.75-3.25(m，1H)，3.45-3.30(m，1H)，3.25-3.10(d，J＝4.8Hz，3H)，2.80-2.65(m，1H)，2.60-2.45(m，1H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝171.53，167.72，134.43，128.70，128.17，118.38，61.46，60.24，51.91，34.42，34.26，21.22，14.54.
Embodiment 56 preparation 2SAC-Lys (4k)
According to the method for embodiment 46, prepare title compound by 2 (Boc-SAC) Lys-OH.ESI-MS(m/e)：433M+H] +.
Figure BDA0000057748460000172
(c＝0.48，CH 3OH).IR(KBr)：2924.09，2532.54，1674.21，1562.34，1458.18，1379.10，1217.08，1128.36，991.41，923.90. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.40-8.20(d，J＝8.5Hz，1H)，7.95-7.85(t，J＝4.8Hz，1H)，6.95-6.90(d，J＝8.7Hz，1H)，6.95-6.80(d，J＝8.1Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.20-4.15(m，1H)，4.15-4.08(m，1H)，4.05-4.00(m，1H)，3.30(s，1H)，3.20-3.10(t，J＝8.2Hz，4H)，2.80-2.60(m，2H)，2.60-2.55(m，4H)，1.80-1.55(m，2H)，1.30-1.20(m，2H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝173.12，172.40，167.88，134.46，134.33，118.45，118.38，60.23，51.91，34.37，34.20，31.73，31.29，28.62，21.48，21.22.
Embodiment 57 preparation SAC-Asp (4l)
Method according to embodiment 46 prepares title compound by Boc-SAC-Asp.ESI-MS(m/e)：420[M+H] +.Mp：124℃
Figure BDA0000057748460000173
(c＝0.52，CH 3OH).IR(KBr)：3369.64，2926.01，1734.01，1651.07，1523.76，1440.83，1402.25，1321.34，1062.78，933.555. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝7.45-7.55(d，J＝5.4Hz，1H)，6.65-6.55(d，J＝7.5Hz，1H)，6.15-6.00(d，J＝5.1Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.85-4.65(m，2H)，4.65-4.45(m，1H)，3.85-3.75(s，3H)，3.75-3.65(s，3H)，3.55-3.45(m，3H)，3.25-3.10(m，4H)，2.55-2.75(m，1H)，1.95-1.75(m，1H)，1.30-1.15(t，J＝6.9Hz，4H). 13CNMR(75MHz，DMSO-d 6)：δ/ppm＝172.16，171,76，169.01，168.40，133.64，134.60，118.08，118.01，52.54，35.79，34.63，34.59，31.95，31.74.
Embodiment 58 preparation SAC-Trp (4m)
Method according to embodiment 46 prepares title compound by Boc-SAC-Trp-OH.ESI-MS(m/e)：348[M+H] +.Mp：123℃
Figure BDA0000057748460000181
(c＝0.53，CH 3OH).IR(KBr)：2920.23，2814.14，2771.71，1489.05，1338.60，1228.66，1207.44，929.69，742.59. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝10.95-10.85(s，1H)，8.30-8.20(m，1H)，7.55-7.45(d，J＝7.5Hz，1H)，7.40-7.35(d，J＝8.1Hz，1H)，7.20-7.15(s，1H)，7.15-6.90(m，3H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.25-3.10(m，4H)，2.80-2.65(m，1H)，2.60-2.45(m，1H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝171.53，167.62，134.43，128.86，128.34，118.38，60.24，55.46，51.91，34.42，31.56，21.22，14.54.
Embodiment 59 preparation SAC-Met (4n)
Method according to embodiment 46 prepares title compound by Boc-SAC-Met-OH.ESI-MS(m/e)：293[M+H] +.
Figure BDA0000057748460000182
(c＝0.52，CH 3OH).IR(KBr)：3331.07，3001.24，3205.69，3028.24，2771.71，2445.74，1739.79，1668.43，1174.65，929.69. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.30-8.20(d，J＝7.8Hz，1H)，7.05-6.95(d，J＝8.4Hz，1H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.25-3.10(d，J＝7.2Hz，2H)，2.80-2.65(m，1H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.88，172.40，167.86，134.46，118.34，65.36，60.21，34.42，33.78，31.64，31.19，29.98，25.81，24.88，21.21，15.62.
Embodiment 60 preparation SAC-Phe (4o)
Method according to embodiment 46 prepares title compound by Boc-SAC-Phe.ESI-MS(m/e)：309[M+H] +.
Figure BDA0000057748460000183
(c＝0.53，CH 3OH).IR(KBr)：2875.86，2333.87，1726.29，1672.28，1548.84，1496.76，1406.11，1215.15，1109.07，991.41，923.90. 1HNMR(300MHz，DMSO-d 6)：δ/ppm＝8.40-8.20(d，J＝7.5Hz，2H)，6.95-6.85(d，J＝8.4Hz，2H)，5.85-5.65(m，1H)，5.25-5.05(m，2H)，4.40-4.25(m，1H)，4.20-4.05(m，1H)，3.65(s，3H)，3.25-3.10(d，J＝7.2Hz，2H)，3.10-3.00(m，2H)，2.80-2.65(m，2H). 13C?NMR(75MHz，DMSO-d 6)：δ/ppm＝172.44，167.82，137.66，134.54，129.74，128.73，127.02，118.27，54.49，51.95，37.02，34.47，32.00，21.56.
The anti-inflammatory activity evaluation experimental of experimental example 1 compound 4a-o of the present invention
Compound 4a-o (embodiment 46-60 is prepared) that the embodiment of the invention is prepared and Frosst) are with saline water wiring solution-forming (2 μ mol/ml); (20 ± 2g) are divided into blank group, Frosst) group and 4a-o group, every group of 15 mouse to male ICR mouse at random.Irritate stomach respectively and give compound 4a-o (dosage is 20 μ mol/kg) or Frosst) (dosage is 165 μ mol/kg) administration after 30 minutes, be coated with 0.03ml YLENE toward the left ear gabarit of small white mouse.After 2 hours with small white mouse cervical vertebra dislocation put to death, two ears with the punch tool of diameter 7mm get circular auricle, weigh, two justify auricles weight difference as the swelling degree.The result lists table 1 in.
Table 1 compound 4a-o is to the restraining effect of mice ear
Figure BDA0000057748460000191
N=15; A) compare P＜0.05 with the NS group; .; .
The anti-inflammatory activity evaluation experimental of experimental example 2 The compounds of this invention 4h various dose
According to the method for experimental example 1 with 4h by 2 μ mol/kg, 20 μ mol/kg ,/three kinds of dosage of 00 μ mol/kg irritate stomach to male ICR mouse, the weight difference of two circle auricles is listed table 2 in.
Table 2 various dose 4h is to the restraining effect of mouse swelling
Figure BDA0000057748460000192
N=15; A) compare P＜0.01 with the NS group; B) compare with 20 μ mol/kg group,, P＜0.01
The hot tail-flick method of experimental example 3 mouse optical radiation is estimated the analgesic activity of 4a-o
Male ICR mouse (20 ± 2g), under experimental temperature, raised one day before the experiment.Mouse is packed in the special stationary magazine creel, outside afterbody is exposed to.The light beam irradiates mouse tail that produces with baby spot when surveying pain, with the stopwatch meter from irradiation begin to the whipping response latency (tail flick latency, TFL).Regulating spot light lamp and mouse back range is 2-6s from making the comparatively sensitive TFL of stimulus intensity.Survey 3 times earlier during the experiment beginning, each 5min at interval gets average as the basic threshold of pain.Compound 4a-o of the present invention is mixed with in the 2 μ mol/ml aqueous solution, gastric infusion, irritate the stomach amount is 0.2ml at every turn, dosage is 20 μ mol/kg.Each test is established the saline water group and is made parallel control.For preventing skin scald, illumination 15s dead line, 30min repetition measurement TFL is to observe medicine analgesia time-effect relationship at interval.With threshold of pain raising rate evaluation medicine analgesia intensity: PTV=AAPT/BPT (PTV=threshold of pain raising rate, BPT=basis threshold of pain, threshold of pain after the AAPT=administration-basic threshold of pain).The result who obtains lists table 3 in.
Experimental result shows that compound 4a-o of the present invention all has clear and definite analgesic activity
The analgesic activity of table 3 The compounds of this invention 4a-o
Figure BDA0000057748460000201
Threshold of pain raising rate is represented n=15 with mean ± SD%; A) compare P＜0.001 with the NA group; B) compare P＜0.01 with the NS group; C) compare P＜0.05 with the NS group.
The analgesic activity experiment of experimental example 4 The compounds of this invention 4h various dose
Adopt experimental example 3 the hot whipping model evaluation of mouse optical radiation the analgesic activity of 2 μ mol/kg, 20 μ mol/kg and three kinds of dosage 4h of 200 μ mol/kg.The result lists table 4 in.
Experimental result shows that The compounds of this invention 4h has dose-dependent analgesic activity.
The analgesic activity of 4h under the table 4 different dosing dosage
Figure BDA0000057748460000211
Threshold of pain raising rate is represented n=10 with mean ± SD%; A) compare P＜0.001 with the NS group; B) compare P＞0.05 with the NS group.

Claims (10)

1. the allyl cysteine amino acid derivative that has anti-inflammatory and antalgic activity, its structural formula are shown in the formula I:
Figure FDA0000057748450000011
formula I
Wherein, R is selected from hydrogen, CH 3, CH (CH 3) 2, CH (CH 3) CH 2CH 3, CH 2CH (CH 3) 2, CH 2C 6H 4-OH-p, CH (OH) CH 3, Indole-5-yl-CH 2, CH 2CH 2CO 2CH 3, CH 2OH, CH 2CH 2CH 2CH 2NHCOCH (NH 2) CH 2SCH 2CHCH 2, CH 2CO 2CH 3, Imidazole-4-yl-CH 2, CH 2CH 2SCH 3Or CH 2C 6H 5
2. synthesize the method for the said allyl cysteine amino acid derivative of claim 1, this method comprises:
1) reaction of L-halfcystine and 3-bromopropylene obtains allyl cysteine;
2) allyl cysteine with (BOC) 2Reaction obtains Boc-SAC;
3) reaction of amino acid and methyl alcohol obtains HClAA-OMe;
4) Boc-SAC and HClAA-OMe condensation obtain Boc-SAC-AA-OMe;
5) Boc-SAC-AA-OMe sloughs formicester and generates Boc-SAC-AA;
6) Boc-SAC-AA is removed Boc, promptly get.
3. according to the described method of claim 2, it is characterized in that: in the step 1) L-halfcystine is reacted three hours formation allyl cysteines with the 3-bromopropylene down at 0 ℃ in ammoniacal liquor.
4. according to the described method of claim 2, it is characterized in that: step 2) in containing the dioxane of alkalescent water allyl cysteine with (BOC) 2Reaction gets Boc-SAC.
5. according to the described method of claim 2, it is characterized in that: under the effect of sulfur oxychloride, amino acid and methyl alcohol reaction obtain HClAA-OMe in the step 3); Wherein, described amino acid is selected from Gly, Ala, Val, Ile, Leu, Tyr, Thr, Pro, Glu, Ser, Lys, Asp, Trp, Met or Phe.
6. according to the described method of claim 2, it is characterized in that: in the presence of DCC and HOBt, Boc-SAC is condensed into Boc-SAC-AA-OMe with HClAA-OMe in anhydrous THF in the step 4).
7. according to the described method of claim 2, it is characterized in that: in containing the basic soln of NaOH, Boc-SAC-AA-OMe sloughs formicester and generates Boc-SAC-AA in the step 5).
8. according to the described method of claim 2, it is characterized in that: in the step 6) in containing the ETHYLE ACETATE of hydrogenchloride Boc-SAC-AA remove Boc and generate SAC-AA.
9. the purposes of the described allyl cysteine amino acid derivative of claim 1 in preparation anti-inflammatory or analgesic.
10. anti-inflammatory or analgesic pharmaceutical composition is characterized in that: go up the described allyl cysteine amino acid derivative of significant quantity claim 1 and pharmaceutically acceptable carrier is formed by treatment.
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CN110681362A (en) * 2019-09-26 2020-01-14 浙江大学 Mixed-mode chromatography medium with carboxyl and indolyl as functional groups

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CN101467991A (en) * 2007-08-02 2009-07-01 复旦大学 Uses of allyl cysteine and analogue thereof in preparing medicament for treating myocardial damage
CN101880315A (en) * 2009-05-08 2010-11-10 北京大学 Branch oligopeptide with analgesic activity, preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101467991A (en) * 2007-08-02 2009-07-01 复旦大学 Uses of allyl cysteine and analogue thereof in preparing medicament for treating myocardial damage
CN101880315A (en) * 2009-05-08 2010-11-10 北京大学 Branch oligopeptide with analgesic activity, preparation method and application thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110681362A (en) * 2019-09-26 2020-01-14 浙江大学 Mixed-mode chromatography medium with carboxyl and indolyl as functional groups

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