Method for the stereoselective synthesis of cyclic amino acids

A process for the preparation of a compound of Formula II

• 418
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises:
• a) adding a cyanoacetate of formula
• 419
• wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula
• 420
• a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of
• 421
• b) adding the product of Step a) above to a mixture of benzylmagnesium chloride, benzylmagnesium bromide, or benzylmagnesium iodide, in a solvent to produce the addition products of formulas
• 422
• and
• 423
• c) adding the products of Step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide and a solvent, and stirring, and then acidifying to produce the carboxylic acids of formulas
• 424
• and
• 425
• adding the products of Step b) above to an acid mixture and stirring to produce the carboxylic acids of formulas (4a)
• 426
• 427
• d) contacting the products of Step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5)
• 428
• [amine-H]+ as the amine salt;
• and
• e) converting the product of Step d) to a carboxylic acid of formula (6)
• 429
• f) adding the product of Step e) to a mixture of a tertiary amine base, a solvent, and diphenylphosphoryl azide (DPPA), and stirring to produce the isocyanate of formula (11)
• 430
• or adding the product of Step e) above to ethyl chloroformate or isobutyl chloroformate and a base in a solvent at a temperature of from −40° C. to 78° C., followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene, and refluxing to produce isocyanate of formula (11)
• 431
• g) adding the product of Step f) to a mixture of a solvent and methanol, and stirring to produce the carbamate of formula (12)
• 432
• h) adding the product of Step g) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium(III) chloride, and stirring to produce the carboxylic acid of formula (13)
• 433
• i) adding the product of Step h) to a mixture of a solvent and aqueous hydrochloric acid, and stirring to produce a compound of formula (IIa)
• 434
• j) converting the product of Step i) to a compound of formula (II)
• 435
• and further converting, if desired, to a pharmaceutically acceptable salt by known means.

A process for the preparation of a compound of Formula II

• 469
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises:
• a) adding a cyanoacetate of formula (A),
• 470
• wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula (1),
• 471
• a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of formula (2)
• 472
• b) adding the product of Step a) above to a mixture of benzylmagnesium chloride, benzylmagnesium bromide, or benzylmagnesium iodide, in a solvent to produce the addition products of formulas (3a)
• 473
• 474
• c) adding the products of Step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide, in a solvent, and stirring, and then acidifying to produce the carboxylic acids of formulas (4a)
• 475
• 476
• adding the products of Step b) above to an acid mixture and stirring to produce the carboxylic acids of formulas (4a)
• 477
• 478
• d) contacting the products of Step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5)
• 479
• + as the amine salt;
• e) converting the product of Step d) to a carboxylic acid of formula (6)
• 480
• f) adding oxalyl chloride to a mixture of the product of Step e), a solvent, and N,N-dimethylformamide (DMF), and stirring to produce the acid chloride of formula (14)
• 481
• g) adding the product of Step f) to a mixture of tert-butyl alcohol, a solvent, and a tertiary amine base, and stirring to produce the ester of formula (15)
• 482
• h) adding the product of Step g) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium(III) chloride, and stirring to produce the carboxylic acid of formula (16)
• 483
• i) adding the product of Step h) to a mixture of a solvent, methanol, and (trimethylsilyl)diazomethane, and stirring to produce the bis ester of formula (17);
• 484
• or adding the product of Step h) to a mixture of iodomethane, a solvent, and a base, and stirring to produce the bis ester of formula (17)
• 485
• j) adding an acid to a mixture of the product from Step i) and a solvent, and stirring to produce the carboxylic acid of formula (18)
• 486
• k) adding the product of Step j) to a mixture of a tertiary amine base, a solvent, and diphenylphosphoryl azide (DPPA) is added, and stirring to produce the isocyanate of formula (19)
• 487
• adding the product of Step j) above to ethyl chloroformate or isobutyl chloroformate and a base in a solvent at a temperature of from −40° C. to 78° C., followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene,
• and refluxing to produce isocyanate of formula (19) NCO;
• 488
• l) adding the product of Step k) to a mixture of a solvent and methanol, and stirring to produce the carbamate of formula (20)
• 489
• m) adding the product of Step 1) to a mixture of a solvent and aqueous hydrochloric acid is added, and stirring to produce a compound of
• 490
• n) converting the product of Step m) to a compound of formula (II)
• 491
• and further converting, if desired, to a pharmaceutically acceptable salt by known means.

A process for the preparation of a compound of Formula III

• 541
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises:
• a) adding a cyanoacetate of formula (A),
• 542
• wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula (21)
• 543
• a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of formula(22)
• 544
• b) adding the product of Step a) above to a mixture of benzylmagnesium chloride or benzylmagnesium iodide, in a solvent to produce the addition of products of formulas (23a)
• 545
• c) adding the products of Step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide, in a solvent, and stirring, and then acidifying to produce the carboxylic acids of formulas (24a)
• 546
• and (24b) t C 02H;
• or
• 547
• adding the products of Step b) above to an acid mixture, and stirring to produce the carboxylic acids of formulas (24a)
• 548
• and (24b)
• 549
• d) contacting the products of Step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (25)
• 550
• salt;
• and
• e) converting the product of Step d) to a carboxylic acid of formula (26)
• 551
• f) adding the product of Step e) to a mixture of iodomethane, a solvent, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and stirring to produce the ester of formula (27)
• 552
• or adding the product of Step e) to methanol and an acid to produce the ester of formula (27)
• 553
• or adding the product of Step e) to a solution of diazomethane or trimethylsilyl-diazomethane in a solvent to produce ester of formula (27)
• 554
• g) adding the product of Step f) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium(III) chloride, and stirring to produce the carboxylic acid of formula (28)
• 555
• h) adding the product of Step g) to a mixture of a tertiary amine base, a solvent, and diphenylphosphoryl azide (DPPA), and stirring to produce the isocyanate of formula (29)
• 556
• or adding the product of Step g) above to ethyl chloroformate or isobutyl chloroformate and a base in a solvent at a temperature of from −40° C. to 78° C., followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene, and refluxing to produce isocyanate of formula (29)
• 557
• i) adding the product of Step h) to a mixture of a solvent and methanol, and stirring to produce the carbamate of formula (30)
• 558
• j) adding the product of Step i) to a mixture of a solvent and aqueous hydrochloric acid, and stirring to produce a compound of
• 559
• k) converting the product of Step j) to a compound of formula (III)
• 560
• and further converting, if desired, to a pharmaceutically acceptable salt by known means.

A process for the preparation of a compound of Formula IV

• 561
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises:
• a) adding a cyanoacetate of formula (A),
• 562
• wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula (21),
• 563
• a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of
• 564
• b) adding the product of Step a) above to a mixture of benzylmagnesium chloride or benzylmagnesium iodide, in a solvent to produce the addition of products of formulas (23a)
• 565
• c) adding the products of Step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide, in a solvent, and stirring, and then acidifying to produce the carboxylic acids of formulas (24a)
• 566
• 567
• adding the products of Step b) above to an acid mixture, and stirring to produce the carboxylic acids of formulas (24a)
• 568
• 569
• d) contacting the products of Step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (25)
• 570
• as the amine salt;
• and
• e) converting the product of Step d) to a carboxylic acid of formula (26)
• 571
• f) adding the product of Step e) to a mixture of a tertiary amine base, a solvent, and diphenylphosphoryl azide (DPPA) is added, and stirring to produce the isocyanate of formula (31)
• 572
• adding the product of Step g) above to ethyl chloroformate or isobutyl chloroformate and a base in a solvent at a temperature of from −40° C. to 78° C., followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene, and refluxing to produce the isocyanate of formula (31)
• 573
• g) adding the product of Step f) to a mixture of a solvent and methanol, and stirring to produce the carbamate of formula (32)
• 574
• h) adding the product of Step g) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium(III) chloride, and stirring to produce the carboxylic acid of
• 575
• i) adding the product of Step h) to a mixture of a solvent and aqueous hydrochloric acid, and stirring to produce a compound of
• 576
• j) converting the product of Step i) to a compound of formula (IV),
• 577
• and further converting, if desired, to a pharmaceutically acceptable salt by known means.

A process for the preparation of a compound of Formula IV

• 578
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises:
• a) adding a cyanoacetate of formula (A)
• 579
• wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of,
• 580
• a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of
• 581
• b) adding the product of Step a) above to a mixture of benzylmagnesium chloride or benzylmagnesium iodide, in a solvent to produce the addition of products of formulas (23a)
• 582
• c) adding the products of Step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide, in a solvent, and stirring, and then acidifying to produce the carboxylic acids of formulas (24a)
• 583
• and
• 584
• adding the products of Step b) above to an acid mixture, and stirring to produce the carboxylic acids of formulas (24a)
• 585
• 586
• d) contacting the products of Step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (25)
• 587
• as the amine salt;
• and
• e) converting the product of Step d) to a carboxylic acid of formula (26)
• 588
• f) adding oxalyl chloride to a mixture of the product of Step e), a solvent, and N,N-dimethylformamide (DMF), and stirring to produce the acid chloride of formula (34)
• 589
• g) adding the product of Step f) to a mixture of tert-butyl alcohol, a solvent, and a tertiary amine base, and stirring to produce the ester of
• 590
• h) adding the product of Step g) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium(III) chloride, and stirring to produce the carboxylic acid of
• 591
• i) adding the product of Step h) to a mixture of a solvent, methanol, and (trimethylsilyl)diazomethane, and stirring to produce the bis ester of formula (37);
• 592
• or adding the product of Step h) to a mixture of iodomethane, a solvent, and a base, and stirring to produce the bis ester of formula (37)
• 593
• j) adding an acid to a mixture of the product from Step i) and a solvent and stirring to produce the carboxylic acid of formula (38)
• 594
• k) adding the product of Step j) to a mixture of a tertiary amine base, a solvent, and diphenylphosphoryl azide (DPPA), and stirring to produce the isocyanate of formula (39);
• 595
• or adding the product of Step j) above to ethyl chloroformate or isobutyl chloroformate and a base in a solvent at a temperature of from −40° C. to 78° C., followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene, and refluxing to produce isocyanate of formula (39)
• 596
• l) adding the product of Step k) to a mixture of a solvent and methanol, and stirring to produce the carbamate of formula (40)
• 597
• m) adding the product of Step 1) to a mixture of a solvent and hydrochloric acid, and stirring to produce a compound of
• 598
• n) converting the product of Step m) to a compound of Formula IV
• 599
• and further converting, if desired, to a pharmaceutically acceptable salt by known means.

A process for the preparation of a compound of formula (6)

• 600
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises:
• a) adding a cyanoacetate of formula (A)
• 601
• wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula (1),
• 602
• a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of
• 603
• b) adding the product of Step a) above to a mixture of benzylmagnesium chloride, benzylmagnesium bromide, or benzylmagnesium iodide, in a solvent to produce the addition products of formulas (3a)
• 604
• and
• 605
• c) adding the products of Step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide, and a solvent, and stirring, and then acidifying to produce the carboxylic acids of formulas (4a)
• 606
• adding the products of Step b) above to an acid mixture and stirring to produce the carboxylic acids of formulas (4a)
• 607
• 608
• d) contacting the products of Step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5)
• 609
• as the amine salt;
• and
• e) converting the product of Step d) to a carboxylic acid of formula (6)
• 610

A process for the preparation of a compound of formula (26)

• 630
• wherein R is C1-C10 alkyl or C1-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises:
• a) adding a cyanoacetate of formula (A),
• 631
• wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula (21),
• 632
• a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of
• 633
• b) adding the product of Step a) above to a mixture of benzylmagnesium chloride or benzylmagnesium iodide, in a solvent to produce the addition of products of formulas (23a)
• 634
• c) adding the products of Step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide, and a solvent, and stirring, and then acidifying to produce the carboxylic acids of formulas (24a)
• 635
• adding the products of Step b) above to an acid mixture, and stirring to produce the carboxylic acids of formulas (24a)
• 636
• 637
• d) contacting the products of Step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (25)
• 638
• as the amine salt;
• and
• e) converting the product of Step d) to a carboxylic acid of formula (26)
• 639

A compound selected from:

• E-Cyano-((R)-3-methyl-cyclopentylidene)-acetic acid ethyl ester;
• Z-Cyano-((R)-3-methyl-cyclopentylidene)-acetic acid ethyl ester;
• (R)-((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-cyano-acetic acid ethyl ester;
• (S)-((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-cyano-acetic acid ethyl ester;
• (R)-((1R,3R)-1-Benzyl-3-methyl-cyclopentyl)-cyano-acetic acid ethyl ester;
• (S)-((1R,3R)-1-Benzyl-3-methyl-cyclopentyl)-cyano-acetic acid ethyl ester;
• ((1S,3R)-1-Isocyanatomethyl-3-methyl-cyclopentylmethyl)-benzene;
• ((1S,3R)-1-Benzyl-3-methyl-cyclopentylmethyl)-carbamic acid methyl ester;
• [(1S,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid;
• ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester;
• (1S,3R)-1-Methoxycarbonylmethyl-3-methyl-cyclopentyl)-acetic acid;
• ((1R,3R)-1-Isocyanatomethyl-3-methyl-cyclopentyl)-acetic acid methyl ester;
• [(1R,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester;
• ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-acetic acid tert-butyl ester;
• [(1S,3R)-1-Carboxymethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester;
• [(1S,3R)-1-Methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester;
• ((1R,3R)-1-Methoxycarbonylmethyl-3-methyl-cyclopentyl)-acetic acid;
• ((1S,3R)-1-Isocyanatomethyl-3-methyl-cyclopentyl)-acetic acid methyl ester;
• and
• [(1S,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester.

A compound selected from:

• ((1R,3R)-1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid;
• ((1R,3R)-1-Aminomethyl-3-methyl-cyclopentyl)- acetic acid hydrochloride;
• ((1R,3R)-1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid;
• ((1R,3R)-1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid hydrochloride;
• ((1R,3R)-1-Aminomethyl-3-propyl-cyclopentyl)-acetic acid;
• and
• ((1R,3R)-1-Aminomethyl-3-propyl-cyclopentyl)-acetic acid hydrochloride.

A compound selected from:

• ((1S,3R)-1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid;
• ((1S,3R)-1-Aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride;
• ((1S,3R)-1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid;
• ((1S,3R)-1-Aminomethyl-3-ethyl-cyclopentyl)-acetic acid hydrochloride;
• ((1S,3R)-1-Aminomethyl-3-propyl-cyclopentyl)-acetic acid;
• and
• ((1S,3R)-1-Aminomethyl-3-propyl-cyclopentyl)-acetic acid hydrochloride.

A process for the preparation of a compound of formula (4a)

• 672
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, comprising, hydrolyzing a compound of formula (3a)
• 673
• wherein R1 is H, alkyl, or benzyl.

A process for the preparation of a compound of formula (24a)

• 674
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, comprising, hydrolyzing a compound of formula (23a)
• 675
• wherein R1 is H, alkyl, or benzyl.

A process for the preparation of a compound of formula (6)

• 676
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, comprising, resolving a mixture containing compounds of formulas (4a)
• 677
• 678
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl.

A process for the preparation of a compound of formula (26)

• 679
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, comprising, resolving a mixture containing compounds of formulas (24a)
• 680
• 681
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl.

A process for the preparation of a compound of Formula I

• 682
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and a pharmaceutically acceptable salts thereof, comprising, hydrolyzing a compound of formula (41)
• 683
• wherein R1 is H, alkyl, or benzyl, and contacting the product, if desired, with an acid or a base.

A process for the preparation of a compound of Formula II

• 684
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and a pharmaceutically acceptable salts thereof, comprising, hydrolyzing a compound of formula (42)
• 685
• is H, alkyl, or benzyl, and contacting the product, if desired, with an acid or a base.

A process for the preparation of a compound of Formula III

• 686
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof;
• comprising, hydrolyzing a compound of formula (43)
• 687
• wherein R1 is H, alkyl, or benzyl, and contacting the product, if desired, with an acid or a base.

A process for the preparation of a compound of Formula IV

• 688
• wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, comprising, hydrolyzing a compound of formula (44),
• 689
• wherein R1 is H, alkyl, or benzyl, and contacting the product, if desired, with an acid or a base.