Claims
- 1. A method for preparing a compound of the formula: ##STR16## said method comprising: (a) reacting alanine methyl ester with oxalyl chloride followed by treatment with ammonia in methanol to yield a compound of the formula: ##STR17## (b) reduction of the amide functionality with diborane in tetrahydrofuran followed by neutralization the tetrachloride salt with sodium ethoxide to yield a compound of the formula (XVIII).
- 2. A method for preparing a compound of the formula: ##STR18## said method comprising: (a) reacting t-BOC-(S)-alanine with isobutylchloroformate in the presence of N-methylmorpholine, followed by reaction with aminoacetonitrile to yield a compound of the formula: ##STR19## (b) reducing the nitrile of (XXI) with palladium hydroxide in acetic acid to yield a compound of the formula: ##STR20## (c) reacting t-BOC-(R)-alanine with 1,1'-carbonyldiimidazole followed by reaction with amine (XXII) to yield a compound of the formula: ##STR21## (d) removing the t-BOC group with mineral acid followed by reduction of the amide function with diborane followed by neutralization of the tetrahydrochloride salt with sodium ethoxide to yield a compound of the formula (XXVI).
- 3. A method for preparing a compound of the formula: ##STR22## said method comprising: (a) reacting (t-BOC)-alaninyl alanine with isobutylchloroformate in the presence of N-methyl morpholine, followed by reaction with (S)-alanine methyl ester to yield a compound of the formula: ##STR23## (b) reacting compound (XXXV) with ammonia in methanol to yield a compound of the formula: ##STR24## (c) reduction of the amide functionality with diborane in tetrahydrofuran followed by neutralization of the tetrahydrochloride salt with sodium ethoxide to yield a compound of the formula (XXXIX).
- 4. A process for preparing the free base form of a compound of formula (IV): ##STR25## comprising the steps of: (a) reacting in solution a compound of the formula: ##STR26## wherein R.sup.10 is an amine protecting group that can be removed without the addition of acid,
- with a suitable carboxyl activating agent, said carboxyl activating agent facilitating the formation of an amide bond,
- followed by reaction with ethylenediamine to yield a compound of formula (XXXXVII): ##STR27## (b) contacting the compound of formula (XXXXVII) with a suitable reagent or combination of reagents to effect the removal, without the addition of acid, of the R.sup.10 amine protecting groups from the compound of formula (XXXXVII) to yield in solution the free base form of the compound of formula (XXXXVIII): ##STR28## (c) isolating the compound of formula (XXXXVIII) by removal of unwanted solids from the reaction medium and contacting the reaction solution with a suitable solvent to effect precipitation of the free base form of the compound of formula (XXXXVIII);
- (d) reacting the resultant compound of formula (XXXXVIII) in solution with a suitable amide reducing agent, said amide reducing agent not resulting in the formation of distillable complexes of the amine reducing agent and the compound of formula (IV), to yield the free base form of the compound of formula (IV).
- 5. A process of claim 4, wherein R.sup.10 is selected from:
- 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate;
- 2-trimethylsilylethyl carbamate;
- 2-phenylethyl carbamate;
- 1,1-dimethyl-2,2-dibromoethyl carbamate;
- 1-methyl-1-(4-biphenylyl)ethyl carbamate;
- benzyl carbamate;
- p-nitrobenzyl carbamate;
- 2-(p-toluenesulfonyl)ethyl carbamate;
- m-chloro-p-acyloxybenzyl carbamate;
- 5-benzyisoxazolylmethyl carbamate;
- p-(dihydroxyboryl)benzyl carbamate;
- m-nitrophenyl carbamate;
- o-nitrobenzyl carbamate;
- 3,5-dimethoxybenzyl carbamate;
- 3,4-dimethoxy-6-nitrobenzyl carbamate;
- N'-p-toluenesulfonylamino-carbonyl;
- t-amyl carbamate;
- p-decyloxybenzyl carbamate;
- diisopropylmethyl carbamate;
- 2,2-dimethoxycarbonylvinyl carbamate;
- di(2-pyridyl)methyl carbamate;
- 2-furanylmethyl carbamate;
- phthalimide;
- dithiasuccinimide;
- 2,5-dimethylpyrrole;
- benzyl;
- 5-dibenzylsuberyl;
- triphenylmethyl;
- benzylidene; or
- diphenylmethylene.
- 6. A process of claim 4, wherein R.sup.10 is selected from:
- 2-phenylethyl carbamate;
- benzyl carbamate;
- p-nitrobenzyl carbamate;
- 2-(p-toluenesulfonyl)ethyl carbamate;
- 5-benzyisoxazolylmethyl carbamate;
- m-nitrophenyl carbamate;
- o-nitrobenzyl carbamate;
- 3,5-dimethoxybenzyl carbamate;
- 3,4-dimethoxy-6-nitrobenzyl carbamate;
- p-decyloxybenzyl carbamate;
- di(2-pyridyl)methyl carbamate;
- 2-furanylmethyl carbamate;
- phthalimide;
- benzyl; or
- diphenylmethylene.
- 7. A process of claim 4 wherein in step (c) the suitable solvent to effect precipitation of the compound of formula (XXXXVIII) is t-butylmethyl ether.
- 8. A process of claim 4 wherein step (c) comprises contacting the reaction solution or solvent exchanging of the reaction solution with t-butylmethyl ether to precipitate the compound of formula (XXXXVIII) followed by separation of solids and liquid to isolate the compound of formula (XXXXVIII).
- 9. A process of claim 4 wherein the amide reducing agent is selected from: lithium aluminum hydride, AlH.sub.3, diisobutyl aluminum hydride, NaAlEt.sub.2 H.sub.2, sodium bis(2-methoxyethoxy)aluminum hydride, or catalytic hydrogenation with Raney nickel of a corresponding thioamide.
- 10. A process of claim 4 wherein the amide reducing agent is lithium aluminum hydride.
- 11. A process of claim 4 wherein the carboxyl activating agent is selected from: N-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline; N-isobutyloxycarbonyl-2-isobutyloxycarbonyl-1,2-dihydroquinoine; isobutyl chlorocarbonate; diphenylphosphorazidate; carbonyldiimidazole; ethoxyacetylene; ethoxyacetylene in combination with 1-hydroxybenzotriazole or N-hydroxysuccinimide; dicyclohexylcarbodiimide; or dicyclohexylcarbodiimide in combination with 1-hydroxybenzotriazole or N-hydroxysuccinimide.
- 12. A process of claim 4 wherein the carboxyl activating agent is selected from: isobutyl chlorocarbonate or 1,1'-carbonyldiimidazole.
- 13. A process of claim 4, wherein R.sup.10 is benzyl carbamate.
CROSS REFERENCE TO EARLIER FIELD APPLICATION
This application is a continuation-in-part of U.S. patent application Ser. No. 08/025,633, filed Feb. 16, 1993, now U.S. Pat. No. 5,329,048, which is a divisional of U.S. patent application Ser. No. 07/805,044, filed Dec. 11, 1991, now U.S. Pat. No. 5,206,249, which is a continuation-in-part of U.S. patent application Ser. No. 07/676,061, filed Mar. 27, 1991, now abandoned. The disclosure of these earlier filed applications is hereby incorporated herein by reference.
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Foreign Referenced Citations (3)
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Divisions (1)
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805044 |
Dec 1991 |
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Continuation in Parts (2)
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Feb 1993 |
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676061 |
Mar 1991 |
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